In silico prediction of splice-altering single nucleotide variants in the human genome

Xueqiu Jian, Eric Boerwinkle, Xiaoming Liu

Research output: Contribution to journalArticlepeer-review

310 Scopus citations


In silico tools have been developed to predict variants that may have an impact on pre-mRNA splicing. The major limitation of the application of these tools to basic research and clinical practice is the difficulty in interpreting the output. Most tools only predict potential splice sites given a DNA sequence without measuring splicing signal changes caused by a variant. Another limitation is the lack of largescale evaluation studies of these tools.We compared eight in silico tools on 2959 single nucleotide variants within splicing consensus regions (scSNVs) using receiver operating characteristic analysis. The Position Weight Matrix model and MaxEntScan outperformed other methods. Two ensemble learning methods, adaptive boosting and random forests, were used to construct models that take advantage of individual methods. Both models further improved prediction, with outputs of directly interpretable prediction scores. We applied our ensemble scores to scSNVs from the Catalogue of Somatic Mutations in Cancer database. Analysis showed that predicted splice-altering scSNVs are enriched in recurrent sc-SNVs and known cancer genes. We pre-computed our ensemble scores for all potential scSNVs across the human genome, providing a whole genome level resource for identifying splice-altering scSNVs discovered from large-scale sequencing studies.

Original languageEnglish (US)
Pages (from-to)13534-13544
Number of pages11
JournalNucleic acids research
Issue number22
StatePublished - Dec 16 2014
Externally publishedYes

ASJC Scopus subject areas

  • Genetics


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