VariantValidator: Accurate validation, mapping, and formatting of sequence variation descriptions

Freeman, Peter; Hart, Reece K.; Gretton, Liam J.; Brookes, Anthony J.; Dalgleish, Raymond

doi:10.1002/humu.23348

Cited by 129 publications

(98 citation statements)

References 18 publications

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“…The following variant types were selected: missense, nonsense, splicing, small indel, small deletion, and small insertion. The build 37 (GRCh37) genomic coordinates of all variants were obtained using Variant Validator version 0.1.3 [14]. At this point, we excluded genes with only one entry with the DM flag in HGMD 2019.1 (n = 8; RP9, TUB, TMEM126A, IDH3B, FOXD3, SSBP1, MIR184, and OVOL2).…”

Section: Obtaining Lists Of Genes and Variants Associated With Inherimentioning

confidence: 99%

Variability in Gene Expression is Associated with Incomplete Penetrance in Inherited Eye Disorders

Green

Sallah

Ellingford

et al. 2020

Genes

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Inherited eye disorders (IED) are a heterogeneous group of Mendelian conditions that are associated with visual impairment. Although these disorders often exhibit incomplete penetrance and variable expressivity, the scale and mechanisms of these phenomena remain largely unknown. Here, we utilize publicly-available genomic and transcriptomic datasets to gain insights into variable penetrance in IED. Variants in a curated set of 340 IED-implicated genes were extracted from the Human Gene Mutation Database (HGMD) 2019.1 and cross-checked with the Genome Aggregation Database (gnomAD) 2.1 control-only dataset. Genes for which >1 variants were encountered in both HGMD and gnomAD were considered to be associated with variable penetrance (n = 56). Variability in gene expression levels was then estimated for the subset of these genes that was found to be adequately expressed in two relevant resources: the Genotype-Tissue Expression (GTEx) and Eye Genotype Expression (EyeGEx) datasets. We found that genes suspected to be associated with variable penetrance tended to have significantly more variability in gene expression levels in the general population (p = 0.0000015); this finding was consistent across tissue types. The results of this study point to the possible influence of cis and/or trans-acting elements on the expressivity of variants causing Mendelian disorders. They also highlight the potential utility of quantifying gene expression as part of the investigation of families showing evidence of variable penetrance.

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Section: Obtaining Lists Of Genes and Variants Associated With Inherimentioning

confidence: 99%

Variability in Gene Expression is Associated with Incomplete Penetrance in Inherited Eye Disorders

Green

Sallah

Ellingford

et al. 2020

Genes

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“…The upgraded hgvs package is developed and tested on Python 2.7+ and Python 3.5+. The Python API provides a flexible software foundation on which to build data processing pipelines or graphical interfaces, such as VariantValidator (Freeman, Hart, Gretton, Brookes, & Dalgleish, ; https://variantvalidator.org/).…”

Section: Discussionmentioning

confidence: 99%

hgvs: A Python package for manipulating sequence variants using HGVS nomenclature: 2018 Update

et al. 2018

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The Human Genome Variation Society (HGVS) nomenclature guidelines encourage the accurate and standard description of DNA, RNA, and protein sequence variants in public variant databases and the scientific literature. Inconsistent application of the HGVS guidelines can lead to misinterpretation of variants in clinical settings. Reliable software tools are essential to ensure consistent application of the HGVS guidelines when reporting and interpreting variants. We present the hgvs Python package, a comprehensive tool for manipulating sequence variants according to the HGVS nomenclature guidelines. Distinguishing features of the hgvs package include: (1) parsing, formatting, validating, and normalizing variants on genome, transcript, and protein sequences; (2) projecting variants between aligned sequences, including those with gapped alignments; (3) flexible installation using remote or local data (fully local installations eliminate network dependencies); (4) extensive automated tests; and (5) open source development by a community from eight organizations worldwide. This report summarizes recent and significant updates to the hgvs package since its original release in 2014, and presents results of extensive validation using clinical relevant variants from ClinVar and HGMD.

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“…The dbSNP (https://www.ncbi.nlm.nih.gov ›NCBI › Variation), Exac (http://exac.broadinstitute.org/), and 1000 Genome project were used for searching the novelty of the detected variants. Variant validator and Mutalyzer (https://mutalyzer.nl/) software were used for accurate validation and formatting of sequence variants nomenclature using HGVS nomenclature. Statistical analysis was performed by statistical package SPSS version .…”

Section: Methodsmentioning

confidence: 99%

Monogenic leptin deficiency in early childhood obesity

et al. 2019

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Summary Background Early childhood obesity is a public health problem worldwide. It affects different aspects of physical and mental child's health. Identifying the etiologies, especially treatable and preventable causes, can direct health professionals toward proper management. Analysis of serum leptin levels and leptin gene mutations is a rapid and easy step toward the diagnosis of congenital leptin deficiency that is considered an important cause in early childhood obesity. Objectives The aim of this study was to diagnose monogenic leptin deficiency in Egyptian children presenting with early onset obesity (EOO). Methods The current cross‐sectional study included 80 children who developed obesity during the first year of life with BMI > 2 SD (for age and sex). The studied population was subjected to history taking, auxological assessment, serum leptin assay, and leptin gene sequencing. Results Ten cases had leptin deficiency (12.5%), while 18 cases showed elevated leptin levels (22.5%). Leptin gene variants in the coding region were identified in 30% of the leptin‐deficient group: two novel homozygous disease‐causing variants (c.104 T > G and c.34 delC) and another previously reported homozygous pathogenic variant (c.313C > T). Conclusion Leptin deficiency is considered a significant cause of monogenic obesity in Egyptian children with early‐onset obesity as the diagnosis of these patients would be a perfect target for recombinant leptin therapy.

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VariantValidator: Accurate validation, mapping, and formatting of sequence variation descriptions

Cited by 129 publications

References 18 publications

Variability in Gene Expression is Associated with Incomplete Penetrance in Inherited Eye Disorders

Variability in Gene Expression is Associated with Incomplete Penetrance in Inherited Eye Disorders

hgvs: A Python package for manipulating sequence variants using HGVS nomenclature: 2018 Update

Monogenic leptin deficiency in early childhood obesity

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