Article ; Online: SpliceVault predicts the precise nature of variant-associated mis-splicing.
2023 Volume 55, Issue 2, Page(s) 324–332
Abstract: Even for essential splice-site variants that are almost guaranteed to alter mRNA splicing, no current method can reliably predict whether exon-skipping, cryptic activation or multiple events will result, greatly complicating clinical interpretation of ... ...
Abstract | Even for essential splice-site variants that are almost guaranteed to alter mRNA splicing, no current method can reliably predict whether exon-skipping, cryptic activation or multiple events will result, greatly complicating clinical interpretation of pathogenicity. Strikingly, ranking the four most common unannotated splicing events across 335,663 reference RNA-sequencing (RNA-seq) samples (300K-RNA Top-4) predicts the nature of variant-associated mis-splicing with 92% sensitivity. The 300K-RNA Top-4 events correctly identify 96% of exon-skipping events and 86% of cryptic splice sites for 140 clinical cases subject to RNA testing, showing higher sensitivity and positive predictive value than SpliceAI. Notably, RNA re-analyses showed we had missed 300K-RNA Top-4 events for several clinical cases tested before the development of this empirical predictive method. Simply, mis-splicing events that happen around a splice site in RNA-seq data are those most likely to be activated by a splice-site variant. The SpliceVault web portal allows users easy access to 300K-RNA for informed splice-site variant interpretation and classification. |
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MeSH term(s) | RNA Splicing/genetics ; RNA Splice Sites/genetics ; Base Sequence ; Alternative Splicing/genetics |
Chemical Substances | RNA Splice Sites |
Language | English |
Publishing date | 2023-02-06 |
Publishing country | United States |
Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't |
ZDB-ID | 1108734-1 |
ISSN | 1546-1718 ; 1061-4036 |
ISSN (online) | 1546-1718 |
ISSN | 1061-4036 |
DOI | 10.1038/s41588-022-01293-8 |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
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