Assessing the Pathogenicity of Insertion and Deletion Variants with the Variant Effect Scoring Tool (VEST-Indel)

Christopher Douville, David L. Masica, Peter D. Stenson, David N. Cooper, Derek M. Gygax, Rick Kim, Michael Ryan, Rachel Karchin

Research output: Contribution to journalArticlepeer-review

48 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)28-35
Number of pages8
JournalHuman mutation
Issue number1
StatePublished - Jan 1 2016


  • Bioinformatics pathogenicity predictor
  • In-frame frameshift
  • Indel
  • Insertion deletion variant
  • Meta-predictor

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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