RT Journal Article SR Electronic T1 Base-specific mutational intolerance near splice-sites clarifies role of non-essential splice nucleotides JF bioRxiv FD Cold Spring Harbor Laboratory SP 129312 DO 10.1101/129312 A1 Sidi Zhang A1 Kaitlin E. Samocha A1 Manuel A. Rivas A1 Konrad J. Karczewski A1 Emma Daly A1 Ben Schmandt A1 Benjamin M. Neale A1 Daniel G. MacArthur A1 Mark J. Daly YR 2017 UL http://biorxiv.org/content/early/2017/04/21/129312.abstract AB 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.