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

Genetic Testing and Molecular Biomarkers
Sarah E FlanaganSian Ellard

Abstract

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. 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. 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. 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 asses...Continue Reading

References

Aug 15, 1992·Proceedings of the National Academy of Sciences of the United States of America·M StoffelS Lesage
Mar 7, 2001·Human Molecular Genetics·S SunyaevP Bork
May 5, 2001·Genome Research·P C Ng, S Henikoff
May 24, 2001·The New England Journal of Medicine·P R NjølstadG I Bell
Mar 5, 2002·Genome Research·Pauline C Ng, Steven Henikoff
Aug 31, 2002·Nucleic Acids Research·Vasily RamenskyShamil Sunyaev
Jun 26, 2003·Nucleic Acids Research·Pauline C Ng, Steven Henikoff
Sep 4, 2003·Genome Research·Paul D ThomasApurva Narechania
Aug 4, 2006·The New England Journal of Medicine·Ewan R PearsonUNKNOWN Neonatal Diabetes International Collaborative Group
Dec 1, 2006·Nucleic Acids Research·Shengting LiJun Wang
Feb 26, 2008·Diabetologia·S EllardUNKNOWN European Molecular Genetics Quality Network (EMQN) MODY group
Apr 25, 2009·Journal of Biomedical Science·C George Priya Doss, Rao Sethumadhavan

❮ Previous
Next ❯

Citations

May 30, 2013·Journal of Molecular Modeling·C George Priya DossN Nagasundaram
Aug 15, 2013·European Journal of Human Genetics : EJHG·Chun T KwokJacqueline S de Belleroche
Nov 17, 2012·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Elizabeth J LeslieJeffrey C Murray
Dec 14, 2012·Journal of Human Genetics·Kui LiFeng-Xia Yao
Jul 19, 2013·Bioinformatics·Manuel A RivasPeter Donnelly
Dec 13, 2005·BMC Bioinformatics·Nameeta ShahInna L Dubchak
Mar 23, 2006·BMC Bioinformatics·Peng YueJohn Moult
Nov 13, 2013·BMC Medical Genetics·Jeana T DaReSi Houn Hahn
Mar 10, 2007·BMC Medical Genetics·Javier CotignolaIrene Orlow
Mar 12, 2008·BMC Cancer·Outi KilpivaaraHeli Nevanlinna
May 17, 2011·Orphanet Journal of Rare Diseases·Crystel BonnetFrançoise Denoyelle
Jun 29, 2011·Anesthesia and Analgesia·Sharon J Hirshey DirksenTyler Pezalski
Jul 20, 2012·PloS One·Jeffrey A RosenfeldTodd M Smith
Aug 1, 2012·PloS One·Anna Ka-Yee KwongVirginia Chun-Nei Wong
Dec 21, 2012·Laboratory Hematology : Official Publication of the International Society for Laboratory Hematology·Saeid AbrounFarahnaz Asghari
Mar 19, 2014·Forensic Science International : Synergy·Dawei WangYingying Tang
Nov 1, 2011·Annual Review of Medicine·Laura Rodriguez-MurilloMaria Karayiorgou
Oct 17, 2013·Expert Opinion on Medical Diagnostics·Alison S Thomas, Atul B Mehta
Sep 19, 2015·Journal of Thrombosis and Haemostasis : JTH·J N LiF L Yu
Nov 19, 2015·Orphanet Journal of Rare Diseases·Emily J ToddGianina Ravenscroft
Jun 23, 2015·Archives of Pathology & Laboratory Medicine·David N LouisMichael J Becich
Aug 19, 2015·American Journal of Medical Genetics. Part a·Neil E BowlesUNKNOWN Baylor Hopkins Centers for Mendelian Genomics
Mar 30, 2011·Rheumatic Diseases Clinics of North America·Andrew Gomez-Vargas, Steven K Baker
Dec 8, 2015·Indian Journal of Pediatrics·Swati BhardwajArvind Bagga
Aug 19, 2011·American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics : the Official Publication of the International Society of Psychiatric Genetics·L S CarrollM J Owen
Jan 29, 2013·Pediatric Diabetes·Suhaimi HussainFatimah Harun
Aug 21, 2012·Movement Disorders : Official Journal of the Movement Disorder Society·Georgia XiromerisiouKailash P Bhatia

❮ Previous
Next ❯

Software Mentioned

SNAP
SIFT
UCSC genome browser
Panther
PolyPhen

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.