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Genet Test Mol Biomarkers. 2010 Aug;14(4):533-7. doi: 10.1089/gtmb.2010.0036.

Using SIFT and PolyPhen to predict loss-of-function and gain-of-function mutations.

Author information

1
Institute of Biomedical and Clinical Science, Peninsula Medical School, University of Exeter, Exeter, United Kingdom. sarah.flanagan@pms.ac.uk

Erratum in

  • Genet Test Mol Biomarkers. 2010 Oct;14(5):730.

Abstract

CONTEXT:

The interpretation of novel missense variants is a challenge with increasing numbers of such variants being identified and a responsibility to report the findings in the context of all available scientific evidence. Various in silico bioinformatic tools have been developed that predict the likely pathogenicity of missense variants; however, their utility within the diagnostic setting requires further investigation.

AIM:

The aim of our study was to test the predictive value of two of these tools, sorting intolerant from tolerant (SIFT) and polymorphism phenotyping (PolyPhen), in a set of 141 missense variants (131 pathogenic, 8 benign) identified in the ABCC8, GCK, and KCNJ11 genes.

METHODS:

Sixty-six of the mutations caused a gain of protein function, while 67 were loss-of-function mutations. The evolutionary conservation at each residue was also investigated using multiple sequence alignments from the UCSC genome browser.

RESULTS:

The sensitivity of SIFT and PolyPhen was reasonably high (69% and 68%, respectively), but their specificity was low (13% and 16%). Both programs were significantly better at predicting loss-of-function mutations than gain-of-function mutations (SIFT, p = 0.001; PolyPhen, p < or = 0.0001). The most reliable method for assessing the likely pathogenicity of a missense variant was to investigate the degree of conservation at the affected residue. Eighty-eight percent of the mutations affected highly conserved residues, while all of the benign variants occurred at residues that were polymorphic across multiple species.

CONCLUSIONS:

Although SIFT and PolyPhen may be useful in prioritizing changes that are likely to cause a loss of protein function, their low specificity means that their predictions should be interpreted with caution and further evidence to support/refute pathogenicity should be sought before reporting novel missense changes.

PMID:
20642364
DOI:
10.1089/gtmb.2010.0036
[Indexed for MEDLINE]
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