dbNSFP v2.0: A Database of Human Non-synonymous SNVs and Their Functional Predictions and Annotations

Liu, Xiaoming; Jian, Xueqiu; Boerwinkle, Eric

doi:10.1002/humu.22376

Cited by 557 publications

(517 citation statements)

References 43 publications

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“…6,7 Annotations were added using an in-house-built annotation database, according to the UCSC RefGene track, dbSNP137 and the dbNSFP (v2.0). 8 We filtered for genes that contained at least two nonsynonymous variants, variants leading to a premature stop codon or splice variants with allele frequencies of o0.01 in dbSNP137 and absence in our in-house database of~200 exomes. The variants located in these genes were further evaluated for the impact on protein function by SIFT and Polyphen2 as predicted by the dbNSFP database.…”

Section: Methodsmentioning

confidence: 99%

Pathogenic CWF19L1 variants as a novel cause of autosomal recessive cerebellar ataxia and atrophy

et al. 2015

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Autosomal recessive cerebellar ataxia (ARCA) is a group of neurological disorders characterized by degeneration or abnormal development of the cerebellum and spinal cord. ARCA is clinically and genetically highly heterogeneous, with over 20 genes involved. Exome sequencing of a girl with ARCA from non-consanguineous Dutch parents revealed two pathogenic variants c.37G4C; p.D13H and c.946A4T; p.K316* in CWF19L1, a gene with an unknown function, recently reported to cause ARCA in a Turkish family. Sanger sequencing showed that the c.37G4C variant was inherited from the father and the c.946A4T variant from the mother. Pathogenicity was based on the damaging effect on protein function as the c.37G4C variant changed the highly conserved, negatively charged aspartic acid to the positively charged histidine and the c.946A4T variant introduced a premature stop codon. In addition, 27 patients with ARCA were tested for pathogenic variants in CWF19L1, however, no pathogenic variants were identified. Our data confirm CWF19L1 as a novel but rare gene causing ARCA. European Journal of Human Genetics (2016) 24, 619-622; doi:10.1038/ejhg.2015.158; published online 22 July 2015 INTRODUCTIONAutosomal recessive cerebellar ataxia (ARCA) is a group of rare, genetically and clinically heterogeneous neurological disorders affecting both the peripheral and central nervous systems, mainly occurring in children and young adults. 1 Clinical manifestations range from progressive cerebellar syndromes, as a key feature, to spinocerebellar symptoms with spasticity, ophthalmoplegia, sensory/motor neuropathy, involuntary movements, seizures, cognitive impairment, skeletal abnormalities and cutaneous disorders. To date, more than 20 genes have been reported to cause ARCA, however, explaining only 40% of cases. 2 Recently, pathogenic variants were described in a novel gene (CWF19L1) in two siblings with autosomal recessive ataxia syndrome. 3 Here, we report a second case, a girl from non-consanguineous Dutch parents, with cerebellar ataxia and atrophy, who was compound heterozygous for pathogenic variants in the CWF19L1 gene. Our results confirm the suggested role of CWF19L1 in rare cases of autosomal recessive cerebellar ataxia.

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Section: Methodsmentioning

confidence: 99%

Pathogenic CWF19L1 variants as a novel cause of autosomal recessive cerebellar ataxia and atrophy

et al. 2015

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“…Further characterization of all non-synonymous variants, new and previously described, included interrogation using the full list of functional prediction algorithms in the dbNSFP database (version 2.7, September 12, 2014) (42,43). This analysis revealed that the majority of new variants and of known, rare missense have potential significance for the protein function, defined as potentially damaging, not tolerated or highly conserved in a number of the functional prediction algorithms.…”

Section: Ngs Resequencing and Analysis Of Pooled Genomic Regionsmentioning

confidence: 99%

Targeted deep resequencing of ALOX5 and ALOX5AP in patients with diabetes and association of rare variants with leukotriene pathways

Postuła

Janicki

Rosiak

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. The aim of the present study was to investigate a possible association between the accumulation of rare coding variants in the genes for arachidonate 5-lipoxygenase (ALOX5) and ALOX5-activating protein (ALOX5AP), and corresponding production of leukotrienes (LTs) in patients with type 2 diabetes mellitus (T2DM) receiving acetylsalicylic therapy. Twenty exons and corresponding introns of the selected genes were resequenced in 303 DNA samples from patients with T2DM using pooled polymerase chain reaction amplification and next-generation sequencing, using an Illumina HiSeq 2000 sequencing system. The observed non-synonymous variants were further confirmed by individual genotyping of DNA samples comprising of all individuals from the original discovery pools. The association between the investigated phenotypes was based on LTB 4 and LTE 4 concentrations, and the accumulation of rare missense variants (genetic burden) in investigated genes was evaluated using statistical collapsing tests. A total of 10 exonic variants were identified for each resequenced gene, including 5 missense and 5 synonymous variants. The rare missense variants did not exhibit statistically significant differences in the accumulation pattern between the patients with low and high LTs concentrations. As the present study only included patients with T2DM, it is unclear whether the absence of observed association between the accumulation of rare missense variants in investigated genes and LT production is associated with diabetic populations only or may also be applied to other populations.

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“…To compare the predictors' performances with the rfPred one, we have used the individual prediction scores (Polyphen2, SIFT, LRT, PhyloP and MutationTaster) coming from dbNSFPv2.0 23 and CADD scores computed via its web-interface 6 . We have then computed the ROC curves and the areas under the curves of the different classifiers thanks to the R package "Hmisc" 24 on the learning dataset and on the validation datasets.…”

Section: Statistical Model Evaluationmentioning

confidence: 99%

“…For some exome positions, one or several pre-calculated scores were missing in dbNSFP 2.0 23 . Because we wanted to be able to use rfPred even if one of the score is missing for a variant position, we have imputed the missing score value by a random forest approach implemented in the R package "yaImpute" 25 , based on a k-NN algorithm.…”

Section: Missing Data Handlingmentioning

confidence: 99%

Rfpred: A Random Forest Approach for Prediction of Missense Variants in Human Exome

Jabot–Hanin

Varet²,

Torès

et al. 2016

Preprint

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Exome sequencing is becoming a standard tool for gene mapping of genetic diseases. Given the vast amount of data generated by Next Generation Sequencing techniques, identification of disease causal variants is like finding a needle in a haystack. The impact assessment and the prioritization of potential pathogenic variants are expected to reduce work in biological validation, which is long and costly. One of the possible approaches to determine the most probable deleterious variants in individual exomes is to use protein function alteration prediction. We propose in this paper to use a machine learning approach, the random forest to build a new meta-score based on five previously described scores (SIFT, Polyphen2, LRT, PhyloP and MutationTaster) and compiled in the dbNSFP database. The functional meta-score was trained on a dataset of 61 500 non-synonymous Single Nucleotide Polymorphisms (SNPs). The random forest method (rfPred) appears to be globally better than each of the classifiers separately or in combination in a logistic regression model, and better than a newly described score (CADD) on independent validation sets. RfPred scores have been pre-calculated for all the possible non-synonymous SNPs of human exome and are freely accessible at the web-server http://www.sbim.fr/rfPred/

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dbNSFP v2.0: A Database of Human Non-synonymous SNVs and Their Functional Predictions and Annotations

Cited by 557 publications

References 43 publications

Pathogenic CWF19L1 variants as a novel cause of autosomal recessive cerebellar ataxia and atrophy

Pathogenic CWF19L1 variants as a novel cause of autosomal recessive cerebellar ataxia and atrophy

Targeted deep resequencing of ALOX5 and ALOX5AP in patients with diabetes and association of rare variants with leukotriene pathways

Rfpred: A Random Forest Approach for Prediction of Missense Variants in Human Exome

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