SIFT web server: predicting effects of amino acid substitutions on proteins

Sim, Ngak-Leng; Kumar, P. Naresh; Hu, Jing; Henikoff, Steven; Schneider, Georg; Ng, Pauline C.

doi:10.1093/nar/gks539

Cited by 1,867 publications

(1,472 citation statements)

References 35 publications

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“…28 P653L PDGFRA can affect protein function, as predicted by four different computational tools. [19][20][21][22] PDGFRA immunoreactivity, variable in inflammatory fibroid polyps and fibrous tumors, and evident in GISTs, was faintly + /negative in non-tumoral tissue (Figures 2e and f, 3g and i, and 4e). Although PDGFRA immunohistochemistry can be problematic, 29 these consistently observed differences in PDGFRA immunoreactivity probably conceal additional events of PDGFRA tumorigenesis in relation to the germline PDGFRA mutation in background.…”

Section: Discussionmentioning

confidence: 97%

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PDGFRA-mutant syndrome

et al. 2015

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Section: Discussionmentioning

confidence: 97%

“…The P653L PDGFRA missense mutation was predicted with four different computational tools: 'SIFT', 19 'PolyPhen-2', 20 'SNPs&GO', 21 and PROVEAN. 22 Further details are reported in Supplementary Materials and Methods.…”

Section: Bioinformatics Analysismentioning

confidence: 99%

PDGFRA-mutant syndrome

et al. 2015

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“…washington.edu) databases. The impact of predicted aa changes on protein structure and function was assessed by SIFT 11 and PolyPhen-2 (http://genetics. bwh.harvard.edu/pph2).…”

Section: Dna Analysismentioning

confidence: 99%

Clinical and ultrastructural spectrum of diffuse lung disease associated with surfactant protein C mutations

et al. 2015

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Genetic defects of surfactant metabolism are associated with a broad range of clinical manifestations, from neonatal respiratory distress syndrome to adult interstitial lung disease. Early therapies may improve symptoms but diagnosis is often delayed owing to phenotype and genotype variability. Our objective was to characterize the cellular/ultrastructural correlates of surfactant protein C (SP-C) mutations in children with idiopathic diffuse lung diseases. We sequenced SFTPC -the gene encoding SP-C -SFTPB and ABCA3, and analyzed morphology, ultrastructure and SP expression in lung tissue when available. We identified eight subjects who were heterozygous for SP-C mutations. Median age at onset and clinical course were variable. None of the mutations were located in the mature peptide-encoding region, but were either in the pro-protein BRICHOS or linker C-terminal domains. Although lung morphology was similar to other genetic surfactant metabolism disorders, electron microscopy studies showed specific anomalies, suggesting surfactant homeostasis disruption, plus trafficking defects in the four subjects with linker domain mutation and protein misfolding in the single BRICHOS mutation carrier in whom material was available. Immunolabeling studies showed increased proSP-C staining in all cases. In two cases, amyloid deposits could be identified. Immunochemistry and ultrastructural studies may be useful for diagnostic purposes and for genotype interpretation.

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“…After identification of variants, allele frequencies were assessed in controls using restriction endonuclease digestion (Ava II) or using HybProbe chemistry and a LightCycler (Roche, Mannheim, Germany). The significance of the identified variant p.R47W was assessed by considering the conservation of the affected amino acid, the nature and location of the change, its rarity assessed in own controls and population-based datasets, and the possible impact of the amino acid substitution by five different mutation prediction tools (Mutation Taster [9], MutPred [10], SIFT [11], Polyphen2 [12], and SNAP [13]). We analyzed p.R47W by checking two large population-based databases, dbSNP (release 138 at http://www.ncbi.nlm.nih.gov/snp) and the Exome Sequencing Project (ESP6500SI-V2 dataset) of the National Heart, Lung and Blood Institute (http://evs.gs.washington.edu/EVS/ [14]).…”

Section: Methodsmentioning

confidence: 99%

CCN1 Mutation is Associated with Atrial Septal Defect

et al. 2014

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The genetic basis of congenital heart disease remains unknown in most of the cases. Recently, a novel mouse model shed new light on the role of CCN1/CYR61, a matricellular regulatory factor, in cardiac morphogenesis. In a candidate gene approach, we analyzed a cohort of 143 patients with atrial septal defects (ASD) by sequencing the coding exons of CCN1. In addition to three frequent polymorphisms, we identified an extremely rare novel heterozygous missense mutation (c.139C>T; p.R47W) in one patient with severe ASD. The mutation leads to an exchange of residues with quite different properties in a highly conserved position of the Nterminal insulin-like growth factor binding protein (IGFBP) module. Further bioinformatic analysis, exclusion of known ASD disease genes as well as the exclusion of the mutation in a very high number of ethnically matched controls (more than 1000 individuals) and in public genetic databases indicates that the p.R47W variant is a probable disease-associated mutation. The report about ASD in mice in heterozygous Ccn1 +/-animals strongly supports this notion. Our study is the first to suggest a relationship between a probable CCN1 mutation and ASD. Our purpose here was to draw attention to CCN1, a gene that we believe may be important for genetic analysis in patients with congenital heart disease.

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SIFT web server: predicting effects of amino acid substitutions on proteins

Cited by 1,867 publications

References 35 publications

PDGFRA-mutant syndrome

PDGFRA-mutant syndrome

Clinical and ultrastructural spectrum of diffuse lung disease associated with surfactant protein C mutations

CCN1 Mutation is Associated with Atrial Septal Defect

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