Assessing the Pathogenicity of Insertion and Deletion Variants with the Variant Effect Scoring Tool (VEST‐Indel). Issue 1 (26th October 2015)

• Record Type: Journal Article
• Authors: Douville, Christopher; Masica, David L.; Stenson, Peter D.; Cooper, David N.; Gygax, Derek M.; Kim, Rick; Ryan, Michael; Karchin, Rachel
• Is Part Of: Human mutation. Volume 37:Issue 1(2016)
• Page Start: 28
• Page End: 35
• Publication Date: 2015-10-26
• Subjects: insertion deletion variant -- indel -- in‐frame frameshift -- bioinformatics pathogenicity predictor -- meta‐predictor; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.22911
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract : We further developed our Variant Effect Scoring Tool (VEST) to include classification of in‐frame and frameshift indels (VEST‐indel) as pathogenic or benign. VEST‐indel includes a new feature for estimating the importance of a gene in human disease, and achieves improved specificity and balanced accuracy relative to existing methods. VEST is available as a standalone application, and as part of the CRAVAT webserver (cravat.us). ABSTRACT: Insertion/deletion variants (indels) alter protein sequence and length, yet are highly prevalent in healthy populations, presenting a challenge to bioinformatics classifiers. Commonly used features—DNA and protein sequence conservation, indel length, and occurrence in repeat regions—are useful for inference of protein damage. However, these features can cause false positives when predicting the impact of indels on disease. Existing methods for indel classification suffer from low specificities, severely limiting clinical utility. Here, we further develop our variant effect scoring tool (VEST) to include the classification of in‐frame and frameshift indels (VEST‐indel) as pathogenic or benign. We apply 24 features, including a new "PubMed" feature, to estimate a gene's importance in human disease. When compared with four existing indel classifiers, our method achieves a drastically reduced false‐positive rate, improving specificity by as much as 90%. This approach of estimating gene importance might be generally applicable to missense and other bioinformatics pathogenicity predictors, which often fail to achieve high specificity. Finally, we tested all possible meta‐predictors that can be obtained from combining the four different indel classifiers using Boolean conjunctions and disjunctions, and derived a meta‐predictor with improved performance over any individual method.