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

Flanagan, Sarah E., Patch, Ann-Marie and Ellard, Sian (2010) Using SIFT and PolyPhen to predict loss-of-function and gain-of-function mutations. Genetic Testing and Molecular Biomarkers, 14 4: 533-537. doi:10.1089/gtmb.2010.0036

Author Flanagan, Sarah E.
Patch, Ann-Marie
Ellard, Sian
Title Using SIFT and PolyPhen to predict loss-of-function and gain-of-function mutations
Journal name Genetic Testing and Molecular Biomarkers   Check publisher's open access policy
ISSN 1945-0265
Publication date 2010-08-01
Sub-type Article (original research)
DOI 10.1089/gtmb.2010.0036
Open Access Status Not yet assessed
Volume 14
Issue 4
Start page 533
End page 537
Total pages 5
Place of publication New Rochelle, NY, United States
Publisher Mary Ann Liebert
Language eng
Formatted 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≤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.
© 2010, Mary Ann Liebert, Inc.
Keyword PolyPhen
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
Institute for Molecular Bioscience - Publications
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Created: Thu, 05 May 2011, 21:26:13 EST by Susan Allen on behalf of Institute for Molecular Bioscience