Pathogenic variants that alter protein code often disrupt splicing

The lack of tools to identify causative variants from sequencing data greatly limits the promise of Precision Medicine. Previous studies suggest one-third of disease alleles alter splicing. We discovered that splicing defects cluster in diseases (e.g. haploinsufficient genes). We analyzed 4,964 published disease-causing exonic mutations using a Massively Parallel Splicing Assay (MaPSy) that showed 81% concordance rate with patient tissue splicing. ~10% of exonic mutations altered splicing, mostly by disrupting multiple stages of the spliceosome assembly. We present the first large-scale characterization of exonic splicing mutations using a novel technology that facilitates variant classification that keeps pace with variant discovery.