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Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP

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Original languageEnglish
Article number2373
Number of pages10
JournalNature Communications
Issue number2373
Publication statusPublished - 30 May 2019


We aimed to develop an efficient, flexible and scalable approach to diagnostic genome-wide sequence analysis of genetically heterogeneous clinical presentations. Here we present G2P (www.ebi.ac.uk/gene2phenotype) as an online system to establish, curate and distribute datasets for diagnostic variant filtering via association of allelic requirement and mutational consequence at a defined locus with phenotypic terms, confidence level and evidence links. An extension to Ensembl Variant Effect Predictor (VEP), VEP-G2P was used to filter both disease-associated and control whole exome sequence (WES) with Developmental Disorders G2P (G2PDD; 2044 entries). VEP-G2PDD shows a sensitivity/precision of 97.3%/33% for de novo and 81.6%/22.7% for inherited pathogenic genotypes respectively. Many of the missing genotypes are likely false-positive pathogenic assignments. The expected number and discriminative features of background genotypes are defined using control WES. Using only human genetic data VEP-G2P performs well compared to other freely-available diagnostic systems and future phenotypic matching capabilities should further enhance performance.

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