AbstractSomatic mutations in non-coding regions and even in exons may have unidentified regulatory consequences which are often overlooked in analysis workflows. Here we present RegTools (www.regtools.org), a free, open-source software package designed to integrate analysis of somatic variants from genomic data with splice junctions from transcriptomic data to identify variants that may cause aberrant splicing. RegTools was applied to over 9,000 tumor samples with both tumor DNA and RNA sequence data. We discovered 235,778 events where a variant significantly increased the splicing of a particular junction, across 158,200 unique variants and 131,212 unique junctions. To characterize these somatic variants and their associated splice isoforms, we annotated them with the Variant Effect Predictor (VEP), SpliceAI, and Genotype-Tissue Expression (GTEx) junction counts and compared our results to other tools that integrate genomic and transcriptomic data. While certain events can be identified by the aforementioned tools, the unbiased nature of RegTools has allowed us to identify novel splice variants and previously unreported patterns of splicing disruption in known cancer drivers, such as TP53, CDKN2A, and B2M, as well as in genes not previously considered cancer-relevant, such as RNF145.