{"GHR Genes": "

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

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

\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.", "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", "Cytoband": "

Cytoband: large chromosomal region visible by microscope.

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Tier Definitions

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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.

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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.

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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.

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* 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", "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.", "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", "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.", "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.

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Publication: Distribution and intensity of constraint in mammalian genomic sequence

\n", "Variant type": "

Variant types shown here:

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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.

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

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

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

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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", "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/", "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", "Transcript": "

A segment\u00a0of DNA that is\u00a0transcribed to RNA. Gene usually have\u00a0many 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.

\n", "Number of Homozygotes": "

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

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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", "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", "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.

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

\n", "Indels": "Insertion or deletion variants.", "Phylop at 5' UTR": "

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

\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", "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-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", "ICGC Somatic": "

The International Cancer Genome Consortium\u00a0somatic mutation database.

\n", "IARC TP53 Somatic": "

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

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The Somatic database contains somatic mutations in sporadic cancers.

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Release notes

\n", "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).", "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", "nonsense": "A single nucleotide change in a protein coding gene that results in a premature STOP codon in the corresponding transcript. ", "PhastCons20way_mammalian": "PhastCons20way scores are based on multiple alignments of 19 mammalian genome sequences to the human genome.", "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.", "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.

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Reference

\n", "1000 genomes": "

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

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

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\n", "Deletion": "A variant where a nucleic acid sequence of the reference genome is deleted.", "stoploss": "A single nucleotide change in a protein coding gene that results in a loss of the corresponding transcript's STOP codon.", "HGVS DNA level": "

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

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

\n", "TSL": "

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

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From the\u00a0Ensembl web page:

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

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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)\"
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\n", "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.", "API link": "

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

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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.

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More information

\n", "Somatic variant": "An acquired genomic alteration that is present only in a subset of cells of the entire organism, such as the tumor cells.", "Gnomad Genomes Allele Number": "

The number of chromosomes in the population.

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

\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", "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.", "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.", "Equivalent indels": "

Insertions and deletions often have multiple equivalent representations.

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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.

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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", "Structural variants": "

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

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DECIPHER
DGV
ClinVar CNVs
ExacCNV

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

\n", "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", "pNull": "

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

\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.", "SNV": "Single Nucleotide Variant. A variant where a single nucleotide is replaced by another one.", "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 ", "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", "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.", "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\".

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Publications:

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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.

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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

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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", "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). ", "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", "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.

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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.

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

\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/

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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.

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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/

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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", "Gene statistics": "

This table summarises the variants reported in UniProt, ClinVar & VarSome 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.

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Methodology

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The aggregate counts are obtained by scanning all the variant classifications in the the UniProt, ClinVar and VarSome 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.

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

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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.

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

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\n", "DGV": "

The Database of Genomic Variants

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

\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", "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.", "Mastermind": "

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

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

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

\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.

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

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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.

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

\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.", "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", "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", "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.

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Reference

\n", "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)", "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", "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.

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Reference

\n", "IARC TP53 Germline": "

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

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The Germline database contains germline pathogenic variants in familial cancers.

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Release notes

\n", "Nearby variants": "

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

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Click on a variant to view its page.

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

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