{"AlphaMissense": "

AlphaMissense is a deep learning model developed by Google DeepMind that predicts the pathogenicity of single nucleotide missense variants.

", "APPRIS": "

APPRIS (Rodriguez, et al.) is a database storing annotations of human splice isoforms.

", "MANE Select": "

The MANE project\u00a0- The Matched Annotation from the\u00a0NCBI\u00a0and\u00a0EMBL-EBI\u00a0(MANE) \u00a0defines a genome wide set of representative transcripts and corresponding proteins for human protein-coding genes.

\n\n

MANE Select:\u00a0The MANE Select set consists of one transcript at each protein-coding locus across the genome that is representative of biology at that locus. This set is useful as a universal standard for clinical reporting, as a default for display on browsers and key genomic resources, and as a starting point for comparative or evolutionary genomics. MANE Select transcripts are identified using computational methods complemented by manual review and discussion.

\n\n

MANE Plus Clinical:\u00a0The MANE Plus Clinical set includes additional transcripts for genes where MANE Select alone is not sufficient to report all \"Pathogenic (P)\" or \"Likely Pathogenic (LP)\" clinical variants available in public resources.

\n\n

( From\u00a0MANE project\u00a0)

", "MANE Plus Clinical": "

\n\n

( From\u00a0MANE project\u00a0)

", "acmgThrottlingMessage": "

You have exceeded the maximum number of queries for which ACMG/AMP\nclassification and publication data is included. This will reset in 24\nhours.

", "modalContentSubtitle": "

", "modalContentBody": "

Version 13.2.0 of VarSome and\u00a0VarSome Clinical\u00a0was released on 27 March 2025.
\nSummary of Key New Features

\n\n

18 updated databases (full list of databases)

\n\n

", "modalContentTitle": "

VarSome & VarSome Clinical v.13.2.0

", "Mondo": "

The Mondo Disease Ontology (Mondo) aims to harmonize disease definitions across the world. It is a semi-automatically constructed ontology that merges in multiple disease resources to yield a coherent merged ontology.

", "M-CAP": "

M-CAP is hybrid ensemble score (details in DOI: 10.1038/ng.3703). Scores range from 0 to 1. The larger the score the more likely the SNP has damaging effect.

", "MetaRNN": "

Our recurrent neural network (RNN) based ensemble prediction score, which incorporated 16 scores (SIFT, Polyphen2_HDIV, Polyphen2_HVAR, MutationAssessor, PROVEAN, VEST4, M-CAP, REVEL, MutPred, MVP, PrimateAI, DEOGEN2, CADD, fathmm-XF, Eigen and GenoCanyon), 8 conservation scores (GERP, phyloP100way_vertebrate, phyloP30way_mammalian, phyloP17way_primate, phastCons100way_vertebrate, phastCons30way_mammalian, phastCons17way_primate and SiPhy), and allele frequency information from the 1000 Genomes Project (1000GP), ExAC, and gnomAD. Larger value means the SNV is more likely to be damaging. Scores range from 0 to 1.

", "JAX CKB Evidence Type": "

Variant Level Evidence: displays all evidence associated with the simple molecular profile.

\n\n

Extended Evidence: displays all the evidence associated with any category a member variant is associated with.

", "tag_help_text": "

VarSome uses a state-of-the-art machine-learning solution to highlight key terms in publications: genes, diseases, phenotypes, chemical compounds etc.
\nThese are not manually curated.

", "Evidence Rating": "

The quality of the underlying published evidence is rated from one to five stars. Please see more here

", "Observed/Expected": "

\u00a0

\n\n

Missense: Observed over expected ratio for missense variants in transcript (obs_mis divided by exp_mis).
Missense in Polyphen: Observed over expected ratio for PolyPhen-2 predicted \"probably damaging\" missense variants in transcript (obs_mis_pphen divided by exp_mis_pphen).
Synonymous: Observed over expected ratio for missense variants in transcript (obs_syn divided by exp_syn).
Loss of Function: Observed over expected ratio for pLoF variants in transcript (obs_lof divided by exp_lof).

", "Expected": "

\u00a0

\n\n

Missense: Number of expected missense variants in transcript.
Missense in Polyphen: Number of expected missense variants in transcript predicted \"probably damaging\" by PolyPhen-2.
Synonymous: Number of expected synonymous variants in transcript.
Loss of Function: Number of expected predicted loss-of-function (pLoF) variants in transcript.

", "Lower Obs/Exp Bound": "

Missense: Lower bound of 90% confidence interval for o/e ratio for missense variants.
Synonymous: Lower bound of 90% confidence interval for o/e ratio for synonymous variants.
Loss of Function: Lower bound of 90% confidence interval for o/e ratio for pLoF variants.

", "Upper Obs/Exp Bound": "

Missense: Upper bound of 90% confidence interval for o/e ratio for missense variants.
Synonymous: Upper bound of 90% confidence interval for o/e ratio for synonymous variants.
Loss of Function: Upper bound of 90% confidence interval for o/e ratio for pLoF variants (lower values indicate more constrained).

", "Z-Score": "

Missense: Z score for missense variants in gene. Higher (more positive) Z scores indicate that the transcript is more intolerant of variation (more constrained).
Synonymous: Z score for synonymous variants in gene. Higher (more positive) Z scores indicate that the transcript is more intolerant of variation (more constrained). Extreme values of syn_z indicate likely data quality issues.
Loss of Function: Z score for pLoF variants in gene. Higher (more positive) Z scores indicate that the transcript is more intolerant of variation (more constrained).

", "Mutation Rate": "

Missense: Mutation rate summed across all missense variants in transcript.
Synonymous: Mutation rate summed across all synonymous variants in transcript.
Loss of Function: Mutation rate summed across all possible pLoF variants in transcript

", "Total Possible in Transcript": "

\u00a0

\n\n

Missense: Number of possible missense variants in transcript.
Missense in Polyphen: Number of possible missense variants in transcript that are predicted \"probably damaging\" by PolyPhen-2.
Synonymous: Number of possible synonymous variants in transcript.
Loss of Function: Number of possible pLoF variants in transcript.

", "Individuals with Heterozygous LOFs": "

The number of individuals with at least one observed heterozygous pLoF variant, but no homozygous pLoF variants, in the transcript.

", "Individuals with Homozygous LOFs": "

The number of individuals with at least one observed homozygous pLoF in the transcript.

", "Individuals with no LOFs": "

The number of individuals with no observed pLoF variants in the transcript.

", "Probability LOF Tolerant": "

Probability that transcript falls into distribution of unconstrained genes (~100% o/e pLoF ratio; computed from gnomAD data).

", "Probability LOF Recessive": "

Probability that transcript falls into distribution of recessive genes (~46% o/e pLoF ratio; computed from gnomAD data).

", "Probability LOF Intolerant": "

Probability of loss-of-function intolerance; probability that transcript falls into distribution of haploinsufficient genes (~9% o/e pLoF ratio; computed from gnomAD data).

\n\n

\u00a0

", "Observed": "

Missense: Number of observed missense variants in transcript.
Missense in Polyphen: Number of observed missense variants in transcript predicted \"probably damaging\" by PolyPhen-2.
Synonymous: Number of observed synonymous variants in transcript.
Loss of Function: Number of observed predicted loss-of-function (pLoF) variants in transcript.

", "Coding exons": "

Number of coding exons in gene.

", "Defined": "

The number of individuals where at least one high-quality genotype (including homozygous reference) is observed at a called site annotated as a pLoF variant.

", "Constraint Flag": "

Reason gene does not have constraint metrics. One of:

\n\n

no_variants: Zero observed synonymous, missense, pLoF variants.
no_exp_syn: Zero expected synonymous variants.
no_exp_mis: Zero expected missense variants.
no_exp_lof: Zero expected pLoF variants.
syn_outlier: Too many or too few synonymous variants; synonymous z score < -5 synonymous z score > 5
mis_too_many: Too many missense variants; missense z score < -5
lof_too_many: Too many pLoF variants; pLoF z score < -5

", "p": "

The estimated proportion of haplotypes with a pLoF variant. Defined as: 1 - sqrt(no_lofs / defined).

", "Sum of pLOFs": "

Sum of allele frequencies of pLoFs in the transcript.

\n\n

African/African-American:\u00a0Sum of allele frequencies of pLoFs in the transcript among African/African-American individuals.
Ashkenazi Jewish:\u00a0Sum of allele frequencies of pLoFs in the transcript among Ashkenazi Jewish individuals.
East Asian:\u00a0Sum of allele frequencies of pLoFs in the transcript among East Asian individuals.
European (Finnish):\u00a0Sum of allele frequencies of pLoFs in the transcript among European (Finnish) individuals.
European (non-Finnish):\u00a0Sum of allele frequencies of pLoFs in the transcript among European (non-Finnish) individuals.
Admixed American:\u00a0Sum of allele frequencies of pLoFs in the transcript among Admixed American individuals.
South Asian:\u00a0Sum of allele frequencies of pLoFs in the transcript among South Asian individuals.
Remaining:\u00a0Sum of allele frequencies of pLoFs in the transcript among Remaining (uncharacterized ancestry) individuals.

", "Indispensability prediction": "

Essential (\"E\") or loss-of-function tolerant (\"N\") based on Gene_indispensability_score.

\n", "Indispensability score": "

A probability prediction of the gene being essential. From doi:10.1371/journal.pcbi.1002886

\n", "Essential mutagenesis": "

Essential (\"E\"), HAP1-Specific essential (\"H\"), KBM7-Specific essential (\"K\"), or Non-essential phenotype-changing (\"N\"), based on large scale mutagenesis experiments. from doi: 10.1126/science.aac7557

\n", "Essential gene CRISPR2": "

Essential (\"E\"), context-Specific essential (\"S\"), or Non-essential phenotype-changing (\"N\") based on large scale CRISPR experiments. from http://dx.doi.org/10.1016/j.cell.2015.11.015

\n", "Essential gene CRISPR": "

Essential (\"E\") or Non-essential phenotype-changing (\"N\") based on large scale CRISPR experiments. from doi: 10.1126/science.aac7041

\n", "Essential gene": "

Essential (\"E\") or Non-essential phenotype-changing (\"N\") based on Mouse Genome Informatics database. from doi:10.1371/journal.pgen.1003484

\n", "GHIS": "

A score predicting the gene haploinsufficiency. The higher the score the more likely the gene is haploinsufficient. (from doi: 10.1093/nar/gkv474)

\n", "HIPred": "

HIPred prediction of haploinsufficiency of the gene. Y(es) or N(o). (from doi:10.1093/bioinformatics/btx028)

\n", "P(HI)": "

Estimated probability of haploinsufficiency of the gene (from doi:10.1371/journal.pgen.1001154)

\n", "LoFtool Score": "

A percentile score for gene intolerance to functional change. The lower the score the higher gene intolerance to functional change. For details see doi: 10.1093/bioinformatics/btv602.

\n", "RVIS EVS percentage": "

The percentile rank of the gene based on RVIS, the higher the percentile the more tolerant to mutational burden the gene is. Based on EVS (ESP6500) data.

\n", "RVIS EVS": "

Residual Variation Intolerance Score, a measure of intolerance of mutational burden, the higher the score the more tolerant to mutational burden the gene is. Based on EVS (ESP6500) data.

\n", "P(rec)": "

Estimated probability that gene is a recessive disease gene.

\n", "Gene damage index score": "

A genome-wide, gene-level metric of the mutational damage that has\u00a0accumulated in the general population\" from doi: 10.1073/pnas.1518646112. The higher the score the less likely the gene is to be responsible for monogenic diseases.

\n", "Mitomap Allele Count": "Allele count in GenBank out of 47412 sequences.", "bstatistic": "

Background selection (B) value estimates from doi.org/10.1371/journal.pgen.1000471.
\nRanges from 0 to 1000. It estimates the expected fraction (*1000) of neutral diversity present at a site. Values close to 0 represent near complete removal of diversity as a result of background selection and values near 1000 indicate the absence of background selection.
\nData from CADD v1.4.

", "STRING Experimental Score": "

The number of interactions with AD genes of the training set from the experimental score of STRING, with a confidence >400 and a maximum of 3 interactions.

\n", "Phylop at 5' UTR": "

The average PhyloP score for mammals across the transcriptional start site (TSS) (+/- 500 bp from the actual site).

\n", "mRNA Half-life": "

A\u00a0high mRNA half-life (>10h) in mouse embryonic stem cells.

\n", "STRING Text Mining Score": "

The number of interactions with AD genes of the training set using the text-mining score of STRING, with a confidence >300 and a maximum of 3 interactors.

\n", "STRING Combined Score": "

The number of interactions with AD genes of the training set from the combined score of STRING, with a confidence >500 and a maximum of 8 interactions.

\n", "Probability of AD": "

Probability of being AD is a probability of a given gene to be associated with autosomal dominant conditions (P(AD)).

\n", "Number Donor / Number Synonymous": "

The ratio between the number of donor site variants and synonymous variants present in ExAC.

\n", "LDA Score": "

The LDA score is the raw score computed for each gene. It is calculated using the final model and the gene-specific features.\u00a0
\nPlease refer to the article for technical details.

\n", "PMKB": "

Tier Definitions

\n\n

Tier 1 - Variants with strong evidence of clinical utility
\nVariants with strong evidence* of clinical actionability for this tumor type, including FDA-approved targeted therapies for this tumor type.
\nVariants with strong evidence* of prognostic significance for this tumor type.
\nVariants recognized as entity-defining molecular alterations by current WHO guidelines for this tumor type.

\n\n

Tier 2 - Variants with potential clinical relevance
\nStrong evidence* of clinical actionability in this tumor or in a different tumor type.
\nKnown investigational studies targeting this variant in this tumor type.
\nVariants may be included in this tier if they are characteristic of a particular tumor type and/or are thought to have functional relevance for this tumor type, but they do not meet criteria for Tier 1.

\n\n

Tier 3 - Variants of undetermined clinical significance
\nThe functional and clinical relevance of these variants are undetermined for this tumor type. These variants are provided in the event that they are proven to be of clinical utility at a later date.

\n\n

* Evidence is considered \u201cstrong\u201d if there is/are:
\nAn FDA-approved therapy included in professional guidelines related to this variant for this tumor type, and/or
\nWell-powered studies with consensus from experts in the field that guide therapy based on this variant as an independent parameter in this tumor type.

\n", "TSL": "

The Ensembl Transcript Support Level (TSL) is an indication of how much evidence supports each transcript.

\n\n

From the\u00a0Ensembl web page:

\n\n

\"The following categories are assigned to each of the evaluated annotations:

\n\n

tsl1\u00a0\u2013 all splice junctions of the transcript are supported by at least one non-suspect mRNA
tsl2\u00a0\u2013 the best supporting mRNA is flagged as suspect or the support is from multiple ESTs
tsl3\u00a0\u2013 the only support is from a single EST
tsl4\u00a0\u2013 the best supporting EST is flagged as suspect
tsl5\u00a0\u2013 no single transcript supports the model structure
tslNA\u00a0\u2013 the transcript was not analysed for one of the following reasons:\n\t
- pseudogene annotation, including transcribed pseudogenes
- human leukocyte antigen (HLA) transcript
- immunoglobin gene transcript
- T-cell receptor transcript
- single-exon transcript (will be included in a future version)\"
\n\t

", "Missense Z-score": "

Deviation of observed counts from the expected number of\u00a0missense variants. Positive Z scores indicate increased constraint (intolerance to variation) and therefore that the gene had fewer variants than expected. Negative Z scores are given to genes that had more variants than expected.

\n", "Splice distance": "

Number of bases\u00a0to the nearest splice site. Negative numbers indicate that the nearest splice site is downstream from the variant.

\n", "Segmental duplications": "

Number of pairs of segmental duplications\u00a0gene is within

\n", "Synonymous Z-score": "

Deviation of observed counts from the expected number of\u00a0synonymous\u00a0variants. Positive Z scores indicate increased constraint (intolerance to variation) and therefore that the gene had fewer variants than expected. Negative Z scores are given to genes that had more variants than expected.

\n", "Mastermind": "

Mastermind Genomic Search Engine allows you to find disease-gene-variant associations from the scientific literature.

\n\n

You can also explore publications on neighboring variants in the same gene.

\n\n

VarSome users can sign up for a Mastermind Free Edition account.

\n", "Structural variants": "

This browser contains copy-number variants and other, mostly\u00a0large, variants from the following sources:

\n\n

DECIPHER
DGV
ClinVar CNVs
ExacCNV

\n\n

In addition, deletions of length 100 bp or more are shown here from the other databases included in the Region Browser above.

\n", "DGV": "

The Database of Genomic Variants

\n\n

http://dgv.tcag.ca/dgv/app/home

\n", "DECIPHER": "

Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth, H.V. et al (2009). Am.J.Hum.Genet 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)\u00a0https://decipher.sanger.ac.uk/

\n\n

Data Display Agreement Notice
\nThese data are only available for display in the Browser, and not for bulk download. Access to bulk data may be obtained directly from DECIPHER(http://decipher.sanger.ac.uk/datasharing/) and is subject to a Data Access Agreement, in which the user certifies that no attemp to identify individual patients will be undertaken. The same restrictions apply to the public data displayed\u00a0[at hosting institution]\u00a0or\u00a0[in this browser]: no one is authorized to attemp to identify patients by any means.

\n\n

This data is made available as soon as possible and may be a pre-publication release. For information on the proper use of DECIPHER data, please see
\nhttp://decipher.sanger.ac.uk/datasharing/

\n\n

The DECIPHER consortium provides these data in good faith as a research tool, but without verifying the accuracy, clinical validity or utility of the data. The DECIPHER consortium, makes no warranty, express or implied, nor assumes ant legal liability or responsibility for any purpose for which the data are used.

\n", "UniProt Protein regions": "

Protein functional domains and other regions from the\u00a0UniProt\u00a0database.

\n\n

\nThis database uses coordinates of the hg38 reference genome; we have used a lift-over tool for hg19, which may have introduced inaccuracies and could not convert about 1% of the protein regions.

\n\n

\nWe do not include the large structural regions (coiled domains, helical regions, beta sheets etc).

\n", "Gene statistics": "

This table summarises the variants reported in\u00a0UniProt, ClinVar, LOVD, MitoMap, VarSome & PubMed user entries for a given gene. This is useful in order to obtain some high-level insights into the modes of pathogenicity for that gene, for example whether synonymous variants mostly benign, or whether the majority of frame-shift variants are pathogenic.

\n\n

Methodology

\n\n

The aggregate counts are obtained by scanning all the variant classifications in the the\u00a0UniProt, ClinVar, LOVD, MitoMap, VarSome & PubMed databases. For each variant we identify which gene(s) it\u00a0is on. We then iterate through all known transcripts for that gene, and identify the coding impacts (frame-shift, non-sense etc.). Finally we aggregate the counts by gene, coding impact and pathogenicity.

\n\n

In order to avoid double-counting, each variant is only recorded once:

\n\n

in the event that the variant is classified differently by several sources, the \u201cmost definitive\u201d classification is picked. If there is still a conflict the most pathogenic classification will supercede the others.
if different transcripts result in multiple coding impacts, we pick the first found in the following order: exon-deletion, non-sense, frame-shift, stop loss, mis-sense, inframe-indel, synonymous, and finally non-coding. This allows regulatory or non-coding sections of genes to still be reported correctly.

\n\n

All ClinVar entries are counted and\u00a0are not filtered by number of stars.

\n\n

\u00a0

", "GHR Genes": "

The Genetics Home Reference is provided by the US National Library of Medicine.

\n\n

It\u00a0provides consumer-friendly information about the effects of genetic variation on human health.

\n", "Variant type": "

Variant types shown here:

\n\n

SNV: Single Nucleotide Variant. A carrier of this variant has a different nucleotide (DNA base) at this single chromosomal\u00a0position than the human reference genome.

\n\n

Deletion: A carrier of this variant has one or more nucleotides (bases) not present at this chromosomal position relative to the human reference genome.

\n\n

Insertion: A carrier of this variant has one or more additional nucleotides (bases) at this chromosomal position relative to the human reference genome.

\n\n

Substitution: Any variant other than the above whose carrier has a different sequence compared to the human reference genome.

\n\n

Homopolymer insertion / deletion: An insertion or deletion in a region of five or more repetitions of the same base. An insertion is shown as a homopolymer in addition if the sequence inserted also consists of one or more copies of the same base as the reference. Insertions and deletions on homopolymers are a significant source of erroneous variant calls (sequencing artefacts) and are therefore flagged here as such.

\n", "Cytoband": "

Cytoband: large chromosomal region visible by microscope.

\n\n

See also this image.

\n", "Number of queries in this region": "

Number of queries on VarSome for the region displayed. This number is updated\u00a0regularly but not instantly.

\n", "Gnomad Genomes Allele Number": "

The number of chromosomes in the population.

\n\n

\nFor a population of 15,496 individuals the total number of chromosomes 1-22 is 30 992

\n", "Gnomad exomes Allele Number": "

The number of chromosomes in the population.

\n\n

\nFor a population of 123,136 individuals, the total number of chromosomes 1-22 is 246 272

\n", "GWAS Catalog": "

The Genome-Wide Association Study Catalog, has been created and maintained by the\u00a0National Human Genome Research Institute and the\u00a0\u00a0European Bioinformatics Institute.

\n\n

It\u00a0is a quality controlled, manually curated, literature-derived collection of all published genome-wide association studies assaying at least 100,000 SNPs and all SNP-trait associations with p-values < 1.0 x 10^-5 (Hindorff et al., 2009).

\n\n

If you use data from this section in your research, please cite this publication:

\n\n

MacArthur J, Bowler E, Cerezo M, Gil L, Hall P, Hastings E, Junkins H, McMahon A, Milano A, Morales J, Pendlington Z, Welter D, Burdett T, Hindorff L, Flicek P, Cunningham F, and Parkinson H.
\nThe new NHGRI-EBI Catalog of published genome-wide association studies (GWAS Catalog).
\nNucleic Acids Research, 2017, Vol. 45 (Database issue): D896-D901.

\n", "CIViC": "

Clinical Interpretations of Variants in Cancer (CIViC)\u00a0is an expert-crowdsourced knowledgebase by the McDonnell Genome Institute at Washington University School of Medicine.

\n\n

For more information, see publication: CIViC is a community knowledgebase for expert crowdsourcing the clinical interpretation of variants in cancer

\n", "DANN Score": "

DANN is a pathogenicity scoring methodology developed by\u00a0Daniel Quang, Yifei Chen and Xiaohui Xie at the University of California,\u00a0Irvine. It is based on deep neural networks.

\n\n

The value range is 0 to 1, with 1 given to the variants predicted to be the most damaging.

\n\n

The authors request that you cite their publication.

\n", "gnomAD Exomes": "

The\u00a0Genome Aggregation Database\u00a0(gnomAD) is a resource developed by an international coalition of investigators, with the goal of aggregating and harmonizing both exome and genome sequencing data from a wide variety of large-scale sequencing projects, and making summary data available for the wider scientific community.

\n\n

The \"gnomAD exomes\" database is the successor to ExAC.

\n\n

The data set provided on this website spans 123,136 exome sequences and 15,496 whole-genome sequences from unrelated individuals sequenced as part of various disease-specific and population genetic studies. The gnomAD Principal Investigators and groups that have contributed data to the current release are listed\u00a0here.

\n\n

The gnomAD consortium\u00a0requests that any use of data obtained from the gnomAD browser cite\u00a0the ExAC paper.

\n", "Publications linked to this variant": "

Publications linked to this variant by users and the VarSome team.

\n\n

If you have published on this variant, linking your publication here will make it known to an audience of thousands of users in research and clinic.

\n", "IARC TP53 Germline": "

The International Agency for Research on Cancer\u00a0database on the TP53 gene.

\n\n

The Germline database contains germline pathogenic variants in familial cancers.

\n\n

Release notes

\n", "IARC TP53 Somatic": "

The International Agency for Research on Cancer\u00a0database on the TP53 gene.

\n\n

The Somatic database contains somatic mutations in sporadic cancers.

\n\n

Release notes

\n", "Variant": "

A variant on VarSome is a difference an\u00a0individual may have in their\u00a0DNA sequence compared to the human reference genome at a specific locus of their genome.

\n\n

Although each individual typically has 5 million variants in their genome, almost all\u00a0variants either have no effect at all on\u00a0the carrier, or they contibute to the natural differences among people.

\n\n

VarSome collects data from a large number of global databases, showing on a single page knowledge accumulated over decades of research in genetics.

\n", "ICGC Somatic": "

The International Cancer Genome Consortium\u00a0somatic mutation database.

\n", "KEGG": "

KEGG pathway is a collection of manually drawn molecular\u00a0pathway maps.

\n\n

It is part of the\u00a0Kyoto Encyclopedia of Genes and Genomes, and it is maintained by the Kanehisa Laboratories at Kyoto University.

\n", "RPKM": "

Reads per kilobase of transcript per million mapped reads.\u00a0This is a metric derived from RNA sequencing analysis. \u00a0It\u00a0is proportional to the\u00a0gene expression level in the respective tissue type. The maximum value for this dataset is\u00a0252378 (for gene HBB).

\n", "pNull": "

The probability of being tolerant of both heterozygous and homozygous loss-of-function variants

\n", "pRec": "

The probability of being intolerant of homozygous, but not heterozygous loss-of-function variants

\n", "pLI": "

The probability of being loss-of-function intolerant (intolerant of both heterozygous and homozygous loss-of-function variants)

\n", "RF score": "

Ensemble learning method Random Forest (RF) is used to construct the model from individual methods and improve predictions. Scores range from 0 to 1 with higher scores indicating higher probability of being a true splice site. Scores >0.6 are considered splice-altering according to the developers.

\n\n

Reference

\n", "ADA score": "

Ensemble learning method adaptive boosting (ADA) is used to construct the model from individual methods and improve predictions. Scores range from 0 to 1 with higher scores indicating higher probability of being a true splice site. Scores >0.6 are considered splice-altering according to the developers.

\n\n

Reference

\n", "dbscSNV": "

Database Splicing Consensus Single Nucleotide Variant (dbscSNV) includes all variants ( ~15million) in the splicing consensus regions (-3 to +8 at the 5' splice site and -12 to +2 at the 3' splice site). The model was constructed on seven already developed splice-site altering SNV prediction tools.

\n\n

Reference

\n", "Nearby variants": "

Variants overlapping or in the vicinity of the queried\u00a0variant.

\n\n

Click on a variant to view its page.

\n\n

Zoom out (and in) and move around using your mouse or trackpad.

\n", "Location": "

For variants in genes, which part of the gene the variant is in.

\n\n

Examples:

\n\n

\"exon 230 of 313, pos 277-286 of 309\": this variant (most likely a deletion of 10bp)\u00a0affects bases 277 to 286 of the reference exon, whose length is 309

\n\n

\"intron 2\u00a0of 16, pos 1\u00a0of 8925\": this variant affects the first base\u00a0of the second intron (between second and third exon), whose length is 8925. This transcript has 16 introns and 17 exons.

\n", "Equivalent indels": "

Insertions and deletions often have multiple equivalent representations.

\n\n

For example, for the\u00a0simple sequence AAAAAAAAA, a deletion of the first base is equivalent to a\u00a0deletion of the second or\u00a0the last base. This is because the resulting\u00a0sequence\u00a0is the same.

\n\n

We have taken\u00a0care to correctly match equivalent indels.\u00a0We match every\u00a0variant you query to its equivalents in all of the databases featured. If the variant you enter does not appear exactly the same in the results, it's because we have replaced it by its equivalent that matches our databases. For example, deletion \u00a013:38320600:AA:\u00a0will appear in position\u00a038320595 rather than the position entered.

\n", "Short link": "

A permanent short link to this web page that you can use to share this query with anyone. Copy / paste it to your email, tweet, etc.

\n", "API link": "

A link to the webpage of our Application Programming Interface (API) for this variant.

\n\n

A software developer can easily include such queries to our database over the internet in order to annotate a large number of variants, or for any other purpose.

\n\n

More information

\n", "Beacon Network": "

A collection of web services (\"beacons\") by institutions who are willing to share whether they have encountered a genomic variant, in order to help enable new\u00a0findings in genomics research. The beacon project is directed by the\u00a0The Global Alliance for Genomics and Health, but individual academic and commercial organisations contribute data from their own beacons.

\n\n

Publication:\u00a0A federated ecosystem for sharing genomic, clinical data

\n", "dbNSFP": "

A database, compiled by\u00a0Xiaoming Liu,\u00a0Xueqiu Jian\u00a0and\u00a0Eric Boerwinkle, and maintained by the Xiaoming Liu at the\u00a0The University of Texas Health Science Center in\u00a0Houston. dbNSFP is \"a database\u00a0developed for functional prediction and annotation of all\u00a0potential non-synonymous single-nucleotide variants (nsSNVs) in the human genome\".

\n\n

Publications:

\n\n

1. Liu X, Jian X, and Boerwinkle E. 2011.\u00a0dbNSFP: a lightweight database of human non-synonymous SNPs and their functional predictions.\u00a0Human Mutation. 32:894-899.

\n\n

2.\u00a0Liu X, Jian X, and Boerwinkle E. 2013.\u00a0dbNSFP v2.0: A Database of Human Non-synonymous SNVs and Their Functional Predictions and Annotations.\u00a0Human Mutation.\u00a034:E2393-E2402.\u00a0

\n\n

3.\u00a0Liu X, Wu C, Li C and Boerwinkle E. 2016.\u00a0dbNSFP v3.0: A One-Stop Database of Functional Predictions and Annotations for Human Non-synonymous and Splice Site SNVs.\u00a0Human Mutation.\u00a037:235-241.

\n", "Number of Homozygotes": "

Number of individuals in the population who are homozygous for the alternate (non-reference) allele.

\n\n

A very low number of homozygotes in all sub-populations with a much higher corresponding allele count\u00a0suggests that this variant may be causative for a recessive condition.

\n", "Allele Frequency": "

Allele Count divided by Allele Number

\n", "Allele Number": "

The number of chromosomes in the population.

\n\n

For a population of\u00a060,706 individuals, the total number of chromosomes 1-22 is 121,412.

\n", "Allele Count": "

The number of chromosomes in the population that contain the alternate (non-reference) allele.

\n", "Coding location": "

The\u00a0position\u00a0of the amino acid(s)\u00a0affected by\u00a0this variant for this transcript and the total number of amino acids in the transcript.

\n\n

For example \"2-4 of 500\" means the variant affects the second, third and fourth\u00a0amino acid in this transcript out of a total of 500.

\n", "Mutation assessor": "

Mutation assessor predicts the functional impact of variation in proteins through sequence conservation of protein homologs. The prediction tool has been trained on variants from the COSMIC database and has been validated on a large set of polymorphic and disease associated variants. Range\u00a0-5.135 to +6.49.

\n", "Deletion": "A variant where a nucleic acid sequence of the reference genome is deleted.", "MedGen": "An NCBI database that organizes information related to human medical genetics, such as description, guidelines, prognosis, diagnosis, and therapy of conditions with a genetic contribution.", "GERP": "

Genomic Evolutionary Rate Profiling (GERP) is a conservation score calculated by quantifying substitution deficits across multiple alignments of orthologues using the genomes of 35\u00a0mammals. It ranges from -12.3 to 6.17, with 6.17 being the most conserved.

\n\n

Publication: Distribution and intensity of constraint in mammalian genomic sequence

\n", "LRT": "

Likelihood ratio test (LRT) predicts deleterious variants through identification of highly conserved amino acid regions using a comparative genomics data set of 32 vertebrate species. Range 0 to 1.

\n", "Insertion": "A variant where a nucleic acid sequence is inserted and does not substitute any nucleotides of the reference genome.", "MutationTaster prediction": "Prediction of MutationTaster according to naive Bayes classifier, which can be either 'disease causing' or 'polymorphism'. The word 'automatic' is added when the effect of the variant has already been clarified.", "MetaSVM": "

MetaSVM is an ensemble score using Support Vector Machine (SVM) to integrate nine prediction scores (SIFT, PolyPhen-2, GERP++, MutationTaster, Mutation Assessor, FATHMM, LRT, SiPhy and PhyloP) and allele frequencies in 1KG database. The tool has been trained on 36,192 SNVs from UniProt. Range\u00a0-2.0058 to +3.0399.

\n", "stoploss": "A single nucleotide change in a protein coding gene that results in a loss of the corresponding transcript's STOP codon.", "ClinVar": "

A database which connects variants with clinical associated phenotypes, maintained by NCBI, the (US)\u00a0National Center for Biotechnology Information. It also provides related supporting evidence and the name of the submitter.

\n", "PhyloP20way_mammalian": "Phylogenetic P-values (PhyloP) is a conservation score based on multiple alignments given a phylogenetic tree that predicts the rate of evolution compared to what is expected under neutral drift using distributions of the number of substitutions based on a phylogenetic hidden Markov model. PhyloP20way scores are based on multiple alignments of 19 mammalian genome sequences to the human genome.", "Gene symbol": "

An abbreviation of the gene name(s) in\u00a0which the variant is located, approved by HGNC, the HUGO Gene Nomenclature Committee. HUGO is the Human Genome Organisation.

\n", "SNOMED_CT": "Systematized NOMenclature of MEDicine Clinical Terms (SNOMED_CT) is a database that provides the most comprehensive, multilingual clinical healthcare terminology in the world including clinical findings, symptoms, diagnoses, procedures and body structures.", "MetaLR": "

MetaLR is an ensemble score using Logistic Regression (LR) to integrate nine prediction scores (SIFT, PolyPhen-2, GERP++, MutationTaster, Mutation Assessor, FATHMM, LRT, SiPhy and PhyloP) and allele frequencies in 1KG database. The tool has been trained on 36,192 SNVs from UniProt. Range 0 to 1.

\n", "PhastCons20way_mammalian": "PhastCons20way scores are based on multiple alignments of 19 mammalian genome sequences to the human genome.", "Rsid": "

A unique identifier\u00a0prefixed by\u00a0'rs' assigned by the dbSNP database to each variant. An rsid may correspond to several alleles;\u00a0an insertion or deletion (\"indel\") may have multiple rsids.

\n", "ALT sequence": "

The nucleotide sequence\u00a0that substitutes the reference sequence at this locus, thus constituting the variant\u00a0(blank for deletions).

\n", "Germline variant": "A genomic variation that is inherited from the parents. It is present in all cells of the organism, including the germ cells, and can be transmitted to the offspring.", "RefSeq transcripts": "A collection of the most comprehensive and well-annotated non-redundant set of transcripts, which are provided by RefSeq, a database built by the NCBI.", "FATHMM-MKL": "

MKL, in addition to the original FATHMM, also predicts noncoding effects by integrating functional annotation information from the ENCODE. Range 0 to 1.

\n", "PROVEAN": "

Protein Variation Effect Analyzer is an in silico tool that predicts how nonsynonymous, MNP, or in-frame indel variant will affect a protein's biological function. The prediction is based on alignment-based scores derived from pairwise sequence alignments between the query sequence and each of the related sequences at the protein level. Range -14 to +14.

\n", "PhyloP100way": "PhyloP100way scores are based on multiple alignments of 99 vertebrate genome sequences to the human genome. The greater the score, the more conserved the site.", "intronic": "A single nucleotide change that resides in the intronic region of the gene.", "FATHMM": "

Functional Analysis through Hidden Markov Models (FATHMM) is an in silico\u00a0tool that predicts the effects of protein missense mutations. It is based on a combination of sequence conservation and 'pathogenicity weights' (which are derived from the relative frequencies of disease-associated and functionally neutral amino acids mapping onto conserved protein domains). Range -16.13 to +10.64.

\n", "HGVS protein level": "

The notation defined here\u00a0by the Human Genome Variation Society (HGVS), based on the position of the variant on the protein.\u00a0A question mark (?) denotes high uncertainty of the impact of this variant in the protein sequence due to a possible disruption to splicing.

", "fitCons-gm": "

Fitcons (FITness CONSequences of functional annotation) identifies genomic regions that are under selective pressure by integrating epigenomic signals from three ENCODE cell lines (GM12878, H1-hESC and HUVEC) with selective pressure inferred using the INSIGHT ((Inference of Natural Selection from Interspersed Genomically coHerent elemenTs) method. Fitcons-gm represents scores from the the GM12878 cell line. This method has been trained on genomes of 54 unrelated human individuals from the 69 sequences released by Complete Genomics. Range\u00a00 to 0.958517.

\n", "SiPhy29way": "SiPhy (SIte-specific PHYlogenetic analysis) is a conservation analysis tool and uses multiple alignment data from deeply sequenced genomes of 29 mammals to detect bases under selection. It models conservation not only as a decrease in the rate of mutation but it also takes into account the pattern of mutations.", "Substitution": "A variant where reference nucleotide(s) are substituted by other nucleotide(s) but is not an SNV. It includes complex variants and multiple nucleotide polymorphisms (MNPs)", "Kaviar": "

Kaviar is a collection of variants from 35 projects (whole exome and whole genome sequencing studies) collecting data from 77,781 unrelated individuals. Kaviar includes data from ExAC and 1000 genomes.

\n\n

Here we inlcude variants with allele count > 3 in the Kaviar database.

\n", "Allele origin": "

Whether the variant is reported as germline or somatic in the ClinVar database.

\n", "missense": "

A single nucleotide change in a protein-coding gene that results in an amino\u00a0acid substitution in the corresponding protein.

\n", "Ensembl": "A database of genomic information for human and model organisms, created as a joint project between the EBI and the Welcome Trust Sanger Institute.", "Ensembl transcripts": "

A large collection of transcripts, including automated and manually curated annotations, maintained by Ensembl, a major genomics database by EMBL, the European Molecular Biology Laboratory.

\n", "Population frequencies": "

Frequency\u00a0of the alternate allele in different sub-populations. This is the number of occurrences of the alternative allele (\"allele count\") divided by the number of chromosomes in the sub-population (\"allele number\").

\n", "fitCons-i6": "Fitcons (FITness CONSequences of functional annotation) identifies genomic regions that are under selective pressure by integrating epigenomic signals from three ENCODE cell lines (GM12878, H1-hESC and HUVEC) with selective pressure inferred using the INSIGHT ((Inference of Natural Selection from Interspersed Genomically coHerent elemenTs) method. Fitcons-i6 represents integrated scores across the three different cell lines. This method has been trained on genomes of 54 unrelated human individuals from the 69 sequences released by Complete Genomics.", "MutationTaster p value": "

The prob value indicates the probability of prediction with values close to 1 corresponding to the most 'secure' predictions. The prob value should not be confused with the probability of error as used in t-test statistics. The value is 1 for 49% of all SNVs in this database.

\n", "VEST3": "The Variant Effect Scoring Tool (VEST3) predicts missense variants and is based on a supervised machine learning algorithm (random forest) that utilizes 86 quantitative sequence features. The training set of this tool includes known deleterious missense variants from the Human Gene Mutation Database and common (>1% allele frequency) variants from the Exome Sequencing Project (ESP) population.", "PhastCons100way": "PhastCons is a program for identifying conserved genomic regions using multiple alignments, given a phylogenetic tree and it is based on a statistical model of sequence evolution called a phylogenetic hidden Markov model (phylo-HMM). PhastCons100way scores are based on 100 vertebrate genomes (including human). ", "SIFT": "

SIFT (sorts intolerant from tolerant) is an in silico prediction tool for nonsynonymous variants based on sequence homology derived from closely related sequences collected through PSI-BLAST. Range 0 to 1 with values less than 0.05 usually\u00a0considered intolerant. 40% of the values in this database are below 0.01.

\n", "UCSC genome browser": "

Interactive website by the University of California,\u00a0Santa Cruz. It provides visualisation of\u00a0the genomic region of interest and a graphical view of known variation, conservation, expression, and epigenetic data.

\n", "dbSNP": "A database built by the NCBI which archives all known short variants found in various genomes, including SNPs, InDels, MNPs and STRs.", "OMIM": "Online Mendelian Inheritance in Man (OMIM) is a comprehensive catalogue of all known Mendelian disorders and focuses on the relationship between phenotype and genotype.", "Indels": "Insertion or deletion variants.", "RefSeq": "

A database built by the NCBI which provides a collection of the most comprehensive and well-annotated non-redundant set of sequences from various genomes at the DNA, RNA and Protein level.

", "Somatic variant": "An acquired genomic alteration that is present only in a subset of cells of the entire organism, such as the tumor cells.", "CADD": "Combined Annotation Dependent Depletion (CADD) predicts the deleteriousness of variants, from diverse annotations of genetic variation, including missense, intronic, Stop-Gain, insertions and deletions. It uses an SVM training algorithm based on 63 annotations (including conservation metrics, regulatory information, transcript information and protein-level scores) and is trained in 65 \"observed\" and \"simulated\" variants.", "Canonical transcripts": "

The transcript(s) defined as canonical for its gene in the RefSeq and Ensembl databases. It is typically the\u00a0longest transcript of a gene that fulfills certain accuracy and consistency criteria.

\n", "REF sequence": "

The nucleotide sequence of the reference genome that is substituted (blank for insertions).

\n", "nonsense": "A single nucleotide change in a protein coding gene that results in a premature STOP codon in the corresponding transcript. ", "Transcript": "

A segment\u00a0of DNA that is\u00a0transcribed to RNA. Genes usually have\u00a0several alternative transcripts derived through different processes, including alternative splicing, exon skipping, and intron retention. Alternative transcripts are effectively different combinations of exons of the same gene.

", "ExAC": "

The Exome Aggregation Consortium, is a database of variants identified in exome sequencing data from 60,706 unrelated individuals. Data have been collected from various disease-specific and population genetic studies, such as The Cancer Genome Atlas (TCGA) and the Exome Sequencing Project (ESP). Data from individuals with severe paediatric diseases have been removed, so this database is a useful reference set of allele frequencies for severe disease studies.

\n\n

Publication:\u00a0Analysis\u00a0of\u00a0protein-coding\u00a0genetic variation\u00a0in\u00a060,706\u00a0humans

\n", "1000 genomes": "

A detailed catalogue of human genetic variation derived from 2,504 unrelated individuals from 26 distinct populations.

\n\n

Publication:\u00a0A\u00a0map\u00a0of\u00a0human genome variation\u00a0from\u00a0population-scale\u00a0sequencing

\n\n

\u00a0

\n", "Orphanet": "A reference portal of rare diseases and orphan drugs providing a wide range of services, from inventory and classification of diseases to assistance-to-diagnosis tools.", "HGVS DNA level": "

The notation\u00a0defined here by the Human Genome Variation Society (HGVS), based on the position of the variant in the transcript.

\n\n

The rules dictate that, if there are several equivalent indels, the position of the 3'-most equivalent should be used.

\n", "MutationTaster": "

An in silico prediction tool for the pathogenicity of a variant based on evolutionary conservation, splice-site, mRNA, protein and regulatory features. The disease potential is predicted by a naive Bayes classifier.

\n", "Clinical genomic database(CGD)": "

The\u00a0Clinical Genomic Database by the (US) National Human Genome Research Institute, is a manually curated database of diseases with known genetic causes. It is focused at the gene level (and not variant level) of medically significant genetic data with available interventions. CGD does not include somatic mutations from cancer studies or genetic associations identified through association-based studies.

\n", "Clinical significance(ClinVar)": "Classification of the variant according to its significance in the relevant disease (ASN.1 terms in brackets). http://www.ncbi.nlm.nih.gov/clinvar/docs/clinsig/", "SNV": "Single Nucleotide Variant. A variant where a single nucleotide is replaced by another one.", "GERP NR": "GERP's corresponding 'neutral rate' score of the site. It can be used to calculate an alternative conservation measure, a scaled GERP RS score (RS/NR ratio).", "GERP RS": "GERP typical score. It quantifies position-specific constraint in terms of rejected substitutions (RS) by estimating the actual number of substitutions at that site and subtracting it from the number expected assuming neutrality "}

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