Consistency of the tools that predict the impact of single nucleotide variants (SNVs) on gene functionality: The BRCA1 gene

Abstract

Single nucleotide variants (SNVs) occurring in a protein coding gene may disrupt its function in multiple ways. Predicting this disruption has been recognized as an important problem in bioinformatics research. Many tools, hereafter p-tools, have been designed to perform these predictions and many of them are now of common use in scientific research, even in clinical applications. This highlights the importance of understanding the semantics of their outputs. To shed light on this issue, two questions are formulated, (i) do p-tools provide similar predictions? (inner consistency), and (ii) are these predictions consistent with the literature? (outer consistency). To answer these, six p-tools are evaluated with exhaustive SNV datasets from the BRCA1 gene. Two indices, called Kall and Kstrong, are proposed to quantify the inner consistency of pairs of p-tools while the outer consistency is quantified by standard information retrieval metrics. While the inner consistency analysis reveals that most of the p-tools are not consistent with each other, the outer consistency analysis reveals they are characterized by a low prediction performance. Although this result highlights the need of improving the prediction performance of individual p-tools, the inner consistency results pave the way to the systematic design of truly diverse ensembles of p-tools that can overcome the limitations of individual members.