VIP-HL: Semi-automated ACMG/AMP variant interpretation platform for genetic hearing loss

Peng, Jiguang; Xiang, Jiale; Jin, Xiangqian; Meng, Junhua; Song, Nana; Chen, Lisha; Tayoun, Ahmad Abou; Peng, Zhiyu

doi:10.22541/au.160682407.73344037/v1

Cited by 3 publications

(5 citation statements)

References 26 publications

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“…10 Of 24 ACMG/AMP criteria, population (PM2, BA1, BS1 and BS2) and computational (PVS1, PM4, PP3, BP3, BP4, and BP7) data criteria were automatically curated by Variant Interpretation Platform for Genetic Hearing Loss (VIP-HL). 18; 19 Criteria related to allelic data (PM3, PS2/PM6 and BP2), functional data (PS3 and BS3), segregation data (PP1 and BS4), phenotypic (PP4 and BP5) and case/control (PS4) data were manually curated from public literature by experienced biocurators. Considering that there are no mutational hot spots or well-studied functional domains without benign variation in GJB2 , 10 PM1 was not activated.…”

Section: Methodsmentioning

confidence: 99%

Comprehensive simulation and interpretation of single nucleotide substitutions in GJB2 reveals the genetic and phenotypic landscape of GJB2-related hearing loss

Xiang

Song

et al. 2021

Preprint

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Genetic variants in the GJB2 gene are the most frequent causes of congenital and childhood hearing loss worldwide. In addition to nonsyndromic hearing loss, GJB2 pathogenic variants are also correlated with syndromic phenotypes, showing high genetic and phenotypic heterogeneity. To comprehensively delineate the genetic and phenotypic landscape of GJB2 variants, we interpreted and manually curated all the 2043 possible single-nucleotide substitution (SNS) coding variants in this gene following the hearing loss-specific ACMG/AMP guidelines. As a result, 61 (3.0%), 188 (9.2%), 1487 (72.8%), 301 (14.7%) and 6 (0.3%) variants were classified as pathogenic, likely pathogenic, variant of uncertain significance, likely benign and benign, respectively. Interestingly, 54% (84/156) of pathogenic/likely pathogenic missense variants were not recorded in ClinVar. Further analysis showed that the second transmembrane domain (TM2) and the 310 helix are highly enriched for pathogenic missense variants. The N-terminal tail and the extracellular loop (E1) showed a high density of variants that are associated with syndromic or dominant nonsyndromic hearing loss. On the other hand, the intracellular loops (CL and CT) were extremely tolerant to variation. Based on this new information, we propose refinements of the guidelines for variant interpretation in GJB2. In summary, our study interpreted all possible SNS variants in the coding region of the GJB2 gene, characterized novel clinically significant (N = 249) and benign or likely benign (N = 307) in this gene, and revealed significant genotype-phenotype correlations at this common hearing loss locus. The interpretation of GJB2 SNS variants in the coding region provides a prototype for genes with similarly high genetic and phenotypic heterogeneity.

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Section: Methodsmentioning

confidence: 99%

Comprehensive simulation and interpretation of single nucleotide substitutions in GJB2 reveals the genetic and phenotypic landscape of GJB2-related hearing loss

Xiang

Song

et al. 2021

Preprint

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“…Data sets. GenOtoScope variant classification was compared to similar tools: (1) Inter-Var, a tool for variant classification tested across a spectrum of phenotypes [13]; (2) VIP-HL, the recently published tool for hearing loss [11]. We benchmarked the accuracy and precision of variant classification on two data sets.…”

Section: Variant Classificationmentioning

confidence: 99%

“…A recently published bioinformatics tool, VIP-HL [ 11 ], automates 13 out of the 24 evidence-based criteria specified for HL. However, VIP-HL is an online tool that accepts only a single variant per time, thus hindering the automatic and time-efficient interpretation of all variants of WES files for a set of investigated patients, for a heterogeneous condition as HL.…”

Section: Introductionmentioning

confidence: 99%

GenOtoScope: Towards automating ACMG classification of variants associated with congenital hearing loss

et al. 2022

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Since next-generation sequencing (NGS) has become widely available, large gene panels containing up to several hundred genes can be sequenced cost-efficiently. However, the interpretation of the often large numbers of sequence variants detected when using NGS is laborious, prone to errors and is often difficult to compare across laboratories. To overcome this challenge, the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) have introduced standards and guidelines for the interpretation of sequencing variants. Additionally, disease-specific refinements have been developed that include accurate thresholds for many criteria, enabling highly automated processing. This is of particular interest for common but heterogeneous disorders such as hearing impairment. With more than 200 genes associated with hearing disorders, the manual inspection of possible causative variants is particularly difficult and time-consuming. To this end, we developed the open-source bioinformatics tool GenOtoScope, which automates the analysis of all ACMG/AMP criteria that can be assessed without further individual patient information or human curator investigation, including the refined loss of function criterion (“PVS1”). Two types of interfaces are provided: (i) a command line application to classify sequence variants in batches for a set of patients and (ii) a user-friendly website to classify single variants. We compared the performance of our tool with two other variant classification tools using two hearing loss data sets, which were manually annotated either by the ClinGen Hearing Loss Gene Curation Expert Panel or the diagnostics unit of our human genetics department. GenOtoScope achieved the best average accuracy and precision for both data sets. Compared to the second-best tool, GenOtoScope improved the accuracy metric by 25.75% and 4.57% and precision metric by 52.11% and 12.13% on the two data sets, respectively. The web interface is accessible via: http://genotoscope.mh-hannover.de:5000 and the command line interface via: https://github.com/damianosmel/GenOtoScope.

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“…Application of these adjusted criteria has been shown to achieve better classification performance compared to the standard evidence-based criteria for known HL-related variants [6]. A recently published bioinformatics tool, VIP-HL [8], automates 13 out of the 24 evidence-based criteria specified for HL. However, VIP-HL is an online tool that accepts only a single variant per time, thus hindering the automatic and time-efficient interpretation of all variants of December 23, 2021 2/26 WES files for a set of investigated patients, for a heterogeneous condition as HL.…”

Section: Introductionmentioning

confidence: 99%

“…Data setsGenOtoScope variant classification was compared to similar tools: (1) InterVar, a tool for variant classification tested across a spectrum of phenotypes[7]; (2) VIP-HL, the recently published tool for hearing loss[8]. We benchmarked the accuracy and precision of variant classification on two data sets.…”

mentioning

confidence: 99%

GenOtoScope: Towards automating ACMG classification of variants associated with congenital hearing loss

Melidis

Landgraf

Schoener-Heinisch

et al. 2021

Preprint

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Since next-generation sequencing (NGS) has become widely available, large gene panels containing up to several hundred genes can be sequenced cost-efficiently. However, the interpretation of the often large numbers of sequence variants detected when using NGS is laborious, prone to errors and often not comparable across laboratories. To overcome this challenge, the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) introduced standards and guidelines for the interpretation of sequencing variants. Further gene- and disease-specific refinements regarding hereditary hearing loss have been developed since then. With more than 200 genes associated with hearing disorders, the manual inspection of possible causative variants is especially difficult and time consuming. We developed an open-source bioinformatics tool GenOtoScope, which automates all ACMG/AMP criteria that can be assessed without further individual patient information or human curator investigation, including the refined loss of function criterion (“PVS1”). Two types of interfaces are provided: (i) a command line application to classify sequence variants in batches for a set of patients and (ii) a user-friendly website to classify single variants. We compared the performance of our tool with two other variant classification tools using two hearing loss data sets, which were manually annotated either by the ClinGen Hearing Loss Gene Curation Expert Panel or the diagnostics unit of our human genetics department. GenOtoScope achieved the best average accuracy and precision for both data sets. Compared to the second-best tool, GenOtoScope improved accuracy metric by 25.75% and 4.57% and precision metric by 52.11% and 12.13% on the two data sets respectively. The web interface is freely accessible. The command line application along with all source code, documentation and example outputs can be found via the project GitHub page.

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VIP-HL: Semi-automated ACMG/AMP variant interpretation platform for genetic hearing loss

Cited by 3 publications

References 26 publications

Comprehensive simulation and interpretation of single nucleotide substitutions in GJB2 reveals the genetic and phenotypic landscape of GJB2-related hearing loss

Comprehensive simulation and interpretation of single nucleotide substitutions in GJB2 reveals the genetic and phenotypic landscape of GJB2-related hearing loss

GenOtoScope: Towards automating ACMG classification of variants associated with congenital hearing loss

GenOtoScope: Towards automating ACMG classification of variants associated with congenital hearing loss

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