TY - JOUR T1 - Base-specific mutational intolerance near splice-sites clarifies role of non-essential splice nucleotides JF - bioRxiv DO - 10.1101/129312 SP - 129312 AU - Sidi Zhang AU - Kaitlin E. Samocha AU - Manuel A. Rivas AU - Konrad J. Karczewski AU - Emma Daly AU - Ben Schmandt AU - Benjamin M. Neale AU - Daniel G. MacArthur AU - Mark J. Daly Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/04/21/129312.abstract N2 - Variation in RNA splicing (i.e., alternative splicing) plays an important role in many diseases. Variants near 5′ and 3′ splice sites often affect splicing, but the effects of these variants on splicing and disease have not been fully characterized beyond the 2 “essential” splice nucleotides flanking each exon. Here we provide quantitative measurements of tolerance to mutational disruptions by position and reference allele-alternative allele combination. We show that certain reference alleles are particularly sensitive to mutations, regardless of the alternative alleles into which they are mutated. Using public RNA-seq data, we demonstrate that individuals carrying such variants have significantly lower levels of the correctly spliced transcript compared to individuals without them, and confirm that these specific substitutions are highly enriched for known Mendelian mutations. Our results propose a more refined definition of the “splice region” and offer a new way to prioritize and provide functional interpretation of variants identified in diagnostic sequencing and association studies. ER -