NCBoost classifies pathogenic non-coding variants in Mendelian diseases through supervised learning on purifying selection signals in humans

State-of-the-art methods assessing pathogenic non-coding variants have mostly been characterized on common disease-associated polymorphisms, yet with modest accuracy and strong positional biases. In this study, we curated 737 high-confidence pathogenic non-coding variants associated with monogenic Mendelian diseases. In addition to interspecies conservation, a comprehensive set of recent and ongoing purifying selection signals in humans is explored, accounting for lineage-specific regulatory elements. Supervised learning using gradient tree boosting on such features achieves a high predictive performance and overcomes positional bias. NCBoost performs consistently across diverse learning and independent testing data sets and outperforms other existing reference methods. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13059-019-1634-2) contains supplementary material, which is available to authorized users.