PMC:6174355 / 14026-18550 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/6174355","sourcedb":"PMC","sourceid":"6174355","source_url":"https://www.ncbi.nlm.nih.gov/pmc/6174355","text":"The Deafness Variation Database\nThe DVD classifies and interprets variants in 152 genes and microRNAs implicated in genetic hearing loss. The included genes are associated with a variety of hearing loss-related phenotypes including NSHL, NSHL mimics, and common forms of syndromic hearing loss (Table S1). 876,139 genetic variants in these genes were extracted from dbSNP, ExAC, 1000 Genomes, ESP, ClinVar, HGMD, and our internal manual curation database.8, 23, 24 All variants were annotated for MAF (from large-scale population databases), variant effect (intronic, UTR, splice-site, missense, nonsense, synonymous, inframe indels, frameshift indels, start loss, stop loss), deleteriousness predictions (dbNSFP), and classification (ClinVar, HGMD, our internal manual curation) (Figure 1).\nAll available data were used to classify variants computationally, with supplemental expert manual curation as detailed in the Material and Methods (Figure 1). We integrated predictions from six algorithms—two assessing conservation (PhyloP and GERP++) and four evaluating deleteriousness (SIFT, PolyPhen-2, MutationTaster, and LRT)—to calculate a composite pathogenicity score (PS) and annotate variants with MAF \u003c 0.5%. Variants with MAFs above this threshold were automatically classified as benign with the exception of known common founder mutations (Figure 1C, Table S2).16 To validate the PS, we plotted all variants classified as pathogenic by MAF and PS (Figure S1) and found that of 3,591 pathogenic variants with predictions from at least five pathogenicity prediction tools, 95.4% have a composite PS ≥ 60%. The calculated sensitivity, specificity, PPV, and NPV were 0.95, 0.51, 0.74, and 0.88, respectively. We used this threshold for variant classification, labeling variants with a MAF \u003c 0.5 and a PS ≤ 40%, based on at least five pathogenicity predictions, as LB.\nIn aggregate, DVD v.8.1 reports 876,139 variants from 152 genes and microRNAs. Of these variants, 7,502 (0.85%) are classified as P, 671 (0.077%) are LP, 15,287 (1.74%) are LB, 156,970 (17.9%) are B, and 695,709 (79.4%) are VUSs (Figure 2A). To assess only medically relevant variants for deafness, we considered only the 97,007 variants within coding and splice-site regions (exons as defined by RefSeq and Ensembl coding transcripts, ±20 bp from exon boundaries, 3′ and 5′ UTRs, and any deep intronic variant classified as P or LP) as these regions are routinely screened in clinical diagnostics settings. We also considered any variant that is P or LP for a phenotype other than deafness as a VUS for the purpose of this analysis. For example, 20 P/LP variants have been reported in MET (MIM: 164860), but only one has been linked to hearing loss. Of 97,007 variants we considered, 6.2% were P (6,045), 0.5% were LP (445), 14.2% were LB (13,823), 4.8% were B (4,628), and 74.3% were VUSs (72,066) (Figure 2B).\nFigure 2 Variant Classification by the DVD\n(A) Fractions of different classification categories for variants in the whole DVD.\n(B) A slightly different picture emerges when only clinically relevant regions and deafness-associated variants (variants that were associated with other non-related deafness phenotypes are excluded) are considered.\n(C) Comparative overview of DVD versus ClinVar. 7,056 classifications from ClinVar were identified within our specified gene regions (each variant in ClinVar with multiple submissions for pathogenicity has been represented by its most pathogenic submission). Of this number, 6,039 ClinVar classifications agreed with the corresponding DVD classification whereas there was disagreement for 1,017 variants.\n(D) Comparative overview of DVD versus HGMD. 7,845 classifications from HGMD were identified within our specified gene regions. Of this number, 7,458 classifications agreed with the corresponding DVD classification and discrepancies were found for 387 variants.\n(E) There were 72 major categorical changes between ClinVar and DVD that resulted in medically significant differences (53 up-classifications and 19 down-classifications).\n(F) 244 medically significant reclassifications were found when DVD was compared to HGMD (2 up-classifications and 242 down-classifications).\n(G) Of the 20% of genes carrying the greatest numbers of medically significant changes, 6 are implicated in Usher syndrome.\nFor (C) through (F), the horizontal arrows show discordant calls, with the number of discordant classifications shown within each arrow; totals are listed to the right of the colored columns.","divisions":[{"label":"title","span":{"begin":0,"end":31}},{"label":"p","span":{"begin":32,"end":791}},{"label":"p","span":{"begin":792,"end":1871}},{"label":"label","span":{"begin":2885,"end":2893}},{"label":"p","span":{"begin":2894,"end":2927}},{"label":"p","span":{"begin":2928,"end":3011}},{"label":"p","span":{"begin":3012,"end":3227}},{"label":"p","span":{"begin":3228,"end":3632}},{"label":"p","span":{"begin":3633,"end":3894}},{"label":"p","span":{"begin":3895,"end":4066}},{"label":"p","span":{"begin":4067,"end":4208}},{"label":"p","span":{"begin":4209,"end":4332}}],"tracks":[{"project":"2_test","denotations":[{"id":"30245029-26969326-2047663","span":{"begin":455,"end":456},"obj":"26969326"},{"id":"30245029-26445815-2047664","span":{"begin":458,"end":460},"obj":"26445815"},{"id":"30245029-26346818-2047665","span":{"begin":462,"end":464},"obj":"26346818"},{"id":"30245029-25262649-2047666","span":{"begin":1369,"end":1371},"obj":"25262649"}],"attributes":[{"subj":"30245029-26969326-2047663","pred":"source","obj":"2_test"},{"subj":"30245029-26445815-2047664","pred":"source","obj":"2_test"},{"subj":"30245029-26346818-2047665","pred":"source","obj":"2_test"},{"subj":"30245029-25262649-2047666","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"2_test","color":"#93ecd6","default":true}]}]}}