DeMAG predicts the effects of variants in clinically actionable genes by integrating structural and evolutionary epistatic features

Interpretation of rare genetic variants remains challenging. Here, the authors develop a supervised variant effect predictor for use in clinically actionable genes which incorporates evolutionary and structural relationships between residues and has balanced specificity and sensitivity. Despite the increasing use of genomic sequencing in clinical practice, the interpretation of rare genetic variants remains challenging even in well-studied disease genes, resulting in many patients with Variants of Uncertain Significance (VUSs). Computational Variant Effect Predictors (VEPs) provide valuable evidence in variant assessment, but they are prone to misclassifying benign variants, contributing to false positives. Here, we develop Deciphering Mutations in Actionable Genes (DeMAG), a supervised classifier for missense variants trained using extensive diagnostic data available in 59 actionable disease genes (American College of Medical Genetics and Genomics Secondary Findings v2.0, ACMG SF v2.0). DeMAG improves performance over existing VEPs by reaching balanced specificity (82%) and sensitivity (94%) on clinical data, and includes a novel epistatic feature, the 'partners score', which leverages evolutionary and structural partnerships of residues. The 'partners score' provides a general framework for modeling epistatic interactions, integrating both clinical and functional information. We provide our tool and predictions for all missense variants in 316 clinically actionable disease genes (demag.org) to facilitate the interpretation of variants and improve clinical decision-making.

Automated summary

The authors develop a supervised variant effect predictor for use in clinically actionable genes using evolutionary and structural relationships between residues. This tool improves performance over existing predictors by reaching balanced specificity and sensitivity on clinical data, and includes a novel feature called the 'partners score' to model epistatic interactions. The predictions for missense variants in 316 clinically actionable disease genes are available on demag.org.