dbNSFP: A lightweight database of human nonsynonymous SNPs and their functional predictions

Liu, Xiaoming; Jian, Xueqiu; Boerwinkle, Eric

doi:10.1002/humu.21517

Cited by 720 publications

(657 citation statements)

References 30 publications

Supporting

Mentioning

641

Contrasting

Unclassified

Order By: Relevance

“…Minor allele frequencies were recorded manually from dbSNP when required. Coding sequence variants were annotated with prediction of pathogenicity based on the SIFT, 19 PolyPhen-2 20 and MutationTaster 21 algorithms using the pre-calculated data provided in dbNSFP 22 (Supplementary Figure S1). …”

Section: Exome Sequencing Assembly and Variant Callingmentioning

confidence: 99%

“…We used a classification system for missense variants using: (1) missense prediction software assessing pathogenicity at the amino-acid level and (2) evolutionary conservation at the nucleotide level. 24 We used the missense prediction programs, PolyPhen-2, SIFT and MutTaster, and the different scores from these tools were derived according to the rules described by Liu et al 22 Results from the three different tools were combined to give a majority vote resulting in a single classification as 'damaging' or 'tolerated' . For the classification based on evolutionary conservation, all variants with a phylo P40.95 were considered conserved (C), otherwise non-conserved (NC).…”

Section: Variant Prioritisationmentioning

confidence: 99%

See 1 more Smart Citation

Exome sequencing in developmental eye disease leads to identification of causal variants in GJA8, CRYGC, PAX6 and CYP1B1

et al. 2013

View full text Add to dashboard Cite

Developmental eye diseases, including cataract/microcornea, Peters anomaly and coloboma/microphthalmia/anophthalmia, are caused by mutations encoding many different signalling and structural proteins in the developing eye. All modes of Mendelian inheritance occur and many are sporadic cases, so provision of accurate recurrence risk information for families and affected individuals is highly challenging. Extreme genetic heterogeneity renders testing for all known disease genes clinically unavailable with traditional methods. We used whole-exome sequencing in 11 unrelated developmental eye disease patients, as it provides a strategy for assessment of multiple disease genes simultaneously. We identified five causative variants in four patients in four different disease genes, GJA8, CRYGC, PAX6 and CYP1B1. This detection rate (36%) is high for a group of patients where clinical testing is frequently not undertaken due to lack of availability and cost. The results affected clinical management in all cases. These variants were detected in the cataract/microcornea and Peters anomaly patients. In two patients with coloboma/microphthalmia, variants in ABCB6 and GDF3 were identified with incomplete penetrance, highlighting the complex inheritance pattern associated with this phenotype. In the coloboma/microphthalmia patients, four other variants were identified in CYP1B1, and CYP1B1 emerged as a candidate gene to be considered as a modifier in coloboma/ microphthalmia.

show abstract

Section: Exome Sequencing Assembly and Variant Callingmentioning

confidence: 99%

Section: Variant Prioritisationmentioning

confidence: 99%

Exome sequencing in developmental eye disease leads to identification of causal variants in GJA8, CRYGC, PAX6 and CYP1B1

et al. 2013

View full text Add to dashboard Cite

show abstract

“…15 Variants were annotated by ANNOVAR 16 and filtered with NCBI dbSNP v.135, the 1000 Genomes Project catalog, and AVSIFT. 17 An average of 4.545 Gb of sequence was generated per affected individual; 99.8% of the total bases passed quality assessment and were aligned to the human reference sequence, and 80% mapped to the targeted exons with a mean coverage of 393. At this depth of coverage, 95% of the targeted bases were sufficiently covered to pass our threshold for variant calling (R103).…”

mentioning

confidence: 99%

Heterozygous Reelin Mutations Cause Autosomal-Dominant Lateral Temporal Epilepsy

Dazzo

Fanciulli²,

Serioli

et al. 2015

The American Journal of Human Genetics

107

View full text Add to dashboard Cite

Autosomal-dominant lateral temporal epilepsy (ADLTE) is a genetic epilepsy syndrome clinically characterized by focal seizures with prominent auditory symptoms. ADLTE is genetically heterogeneous, and mutations in LGI1 account for fewer than 50% of affected families. Here, we report the identification of causal mutations in reelin (RELN) in seven ADLTE-affected families without LGI1 mutations. We initially investigated 13 ADLTE-affected families by performing SNP-array linkage analysis and whole-exome sequencing and identified three heterozygous missense mutations co-segregating with the syndrome. Subsequent analysis of 15 small ADLTE-affected families revealed four additional missense mutations. 3D modeling predicted that all mutations have structural effects on protein-domain folding. Overall, RELN mutations occurred in 7/40 (17.5%) ADLTE-affected families. RELN encodes a secreted protein, Reelin, which has important functions in both the developing and adult brain and is also found in the blood serum. We show that ADLTE-related mutations significantly decrease serum levels of Reelin, suggesting an inhibitory effect of mutations on protein secretion. We also show that Reelin and LGI1 co-localize in a subset of rat brain neurons, supporting an involvement of both proteins in a common molecular pathway underlying ADLTE. Homozygous RELN mutations are known to cause lissencephaly with cerebellar hypoplasia. Our findings extend the spectrum of neurological disorders associated with RELN mutations and establish a link between RELN and LGI1, which play key regulatory roles in both the developing and adult brain.Temporal-lobe epilepsy is the most common type of focal epilepsy. It is sometimes associated with structural brain lesions, but genetic forms have also been described. Familial temporal-lobe epilepsy comprises two genetically distinct syndromes: familial mesial temporal-lobe epilepsy (FMTLE [MIM: 611630]) 1 and autosomal-dominant lateral temporal epilepsy (ADLTE [MIM: 600512]), also named autosomal-dominant partial epilepsy with auditory features (ADPEAF). 2 ADLTE is a well-defined epileptic syndrome clinically characterized by focal seizures with prominent auditory and/or aphasic symptoms, normal brain MRI, and relatively benign evolution. 2,3 Its inheritance pattern is autosomal dominant with reduced penetrance (around 70%). Mutations associated with ADLTE are found in leucine-rich, glioma inactivated 1 (LGI1 [MIM: 604619]) 4-6 in 30%-50% of ADLTE-affected families. 3,7,8 Other genes harboring ADLTE-causing mutations are unknown.LGI1 is expressed mainly in neurons, particularly in the neocortex and limbic regions, 4,9 and its protein product, LGI1, is secreted. 9 LGI1 has been implicated in the transmission of K þ and AMPA synaptic currents 10,11 and in the regulation of post-natal maturation of cortical excitatory synapses and dendrite pruning. 12 However, it is not known which of these functions underlies ADLTE. Identification of additional genes whose mutations cause ADLTE will help to clarify the pathoge...

show abstract

“…For each of these variants, a score has been attributed with the five following methods: SIFT (released August 2011) 9 , Polyphen2 (HumDiv classifier model v2.1.0) 10 , Mutation Taster (released March 2010) 11 , LRT (released November 2009) 12 and PhyloP 13 thanks to the dbNSFP public database https://sites.google.com/site/jpopgen/dbNSFP. 4 . This database contains all possible SNPs within human genome coding regions, which have been determined by the CCDS project 14 , and for each of the 87 million SNPs, the scores of the five predictors have been pre-calculated and made available.…”

Section: Data Collection For Model Buildingmentioning

confidence: 99%

“…Many different methods have been developed and published over the past fifteen years, each of these has distinct advantages and disadvantages, but none can be considered as the gold standard 123 . The prediction scores of some of these methods have been compiled in the dbNSFP database for all known protein coding genome positions 4 . Besides, Li and colleagues proposed to combine five of them in a logistic regression framework 5 in order to globally improve predictive performance in comparison with individual scores.…”

Section: Introductionmentioning

confidence: 99%

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

Jabot–Hanin

Varet²,

Torès

et al. 2016

Preprint

View full text Add to dashboard Cite

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/

show abstract

dbNSFP: A lightweight database of human nonsynonymous SNPs and their functional predictions

Cited by 720 publications

References 30 publications

Exome sequencing in developmental eye disease leads to identification of causal variants in GJA8, CRYGC, PAX6 and CYP1B1

Exome sequencing in developmental eye disease leads to identification of causal variants in GJA8, CRYGC, PAX6 and CYP1B1

Heterozygous Reelin Mutations Cause Autosomal-Dominant Lateral Temporal Epilepsy

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

Contact Info

Product

Resources

About