Variant Score Ranker—a web application for intuitive missense variant prioritization

Du, Juanjiangmeng; Sudarsanam, Monica; Pérez‐Palma, Eduardo; Ganna, Andrea; Francioli, Laurent C.; Iqbal, Sumaiya; Niestroj, Lisa‐Marie; Leu, Costin; Weisburd, Ben; Poterba, Timothy; Nürnberg, Peter; Daly, Mark J.; Palotie, Aarno; Lal, Dennis

doi:10.1093/bioinformatics/btz252

Cited by 5 publications

(4 citation statements)

References 7 publications

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“…For a well-described monogenic disease space such as IRDs, MATK outperforms Exomiser in finding likely pathogenic variants. Other software such as Variant Score Ranker, 31 Variant Ranker, 32 Diploid Moon (https://www.diploid.com/moon), and EmedGene (https:// www.emedgene.com/) have been developed in recent years to address the issue of variant prioritization and new gene discovery, and programs such as PathoMAN 14 are designed to classify variants according to the ACMG/AMP guidelines. 13 There has been great success in using such programs to help find disease causing variants.…”

Section: Discussionmentioning

confidence: 99%

The importance of automation in genetic diagnosis: Lessons from analyzing an inherited retinal degeneration cohort with the Mendelian Analysis Toolkit (MATK)

Zampaglione

Maher

Place

et al. 2022

Genetics in Medicine

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In Mendelian disease diagnosis, variant analysis is a repetitive, error-prone, and time consuming process. To address this, we have developed the Mendelian Analysis Toolkit (MATK), a configurable, automated variant ranking program. Methods: MATK aggregates variant information from multiple annotation sources and uses expert-designed rules with parameterized weights to produce a ranked list of potentially causal solutions. MATK performance was measured by a comparison between MATK-aided and human-domain expert analyses of 1060 families with inherited retinal degeneration (IRD), analyzed using an IRD-specific gene panel (589 individuals) and exome sequencing (471 families). Results: When comparing MATK-assisted analysis with expert curation in both the IRDspecific gene panel and exome sequencing (1060 subjects), 97.3% of potential solutions found by experts were also identified by the MATK-assisted analysis (541 solutions identified with MATK of 556 solutions found by conventional analysis). Furthermore, MATK-assisted analysis identified 114 additional potential solutions from the 504 cases unsolved by conventional analysis. Conclusion: MATK expedites the process of identification of likely solving variants in Mendelian traits, and reduces variability stemming from human error and researcher bias. MATK facilitates data reanalysis to keep up with the constantly improving annotation sources and nextgeneration sequencing processing pipelines. The software is open source and available at https:// gitlab.com/matthew_maher/mendelanalysis.

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Section: Discussionmentioning

confidence: 99%

The importance of automation in genetic diagnosis: Lessons from analyzing an inherited retinal degeneration cohort with the Mendelian Analysis Toolkit (MATK)

Zampaglione

Maher

Place

et al. 2022

Genetics in Medicine

View full text Add to dashboard Cite

show abstract

“…For a well-described monogenic disease space such as IRDs, MATK outperforms Exomiser in finding likely pathogenic variants. Other software such as Variant Score Ranker 31 , Variant Ranker 32 , Diploid Moon, and EmedGene, have been developed in recent years to address the issue of variant prioritization and new gene discovery, and programs such as PathoMAN 14 are designed to classify variants according to ACMG/AMP guidelines 13 . There has been great success in using such programs to help find disease causing variants 33,34 .…”

Section: Discussionmentioning

confidence: 99%

The Importance of Automation in Genetic Diagnosis: Lessons from Analyzing an Inherited Retinal Degeneration Cohort with the Mendelian Analysis Toolkit (MATK)

Zampaglione

Maher

Place

et al. 2021

Preprint

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Purpose: In Mendelian disease diagnosis, variant analysis is a repetitive, error-prone, and time-consuming process. To address this, we have developed the Mendelian Analysis Toolkit (MATK), a configurable automated variant ranking program. Methods: MATK aggregates variant information from multiple annotation sources and uses expert-designed rules with parameterized weights to produce a ranked list of potentially causal solutions. MATK performance was measured by a comparison of MATK-aided versus human domain-expert analyses of 1060 inherited retinal degeneration (IRD) families investigated with an IRD-specific gene panel (589 families) and exome sequencing (471 families). Results: When comparing MATK-assisted analysis to expert curation, we found that 97.3% (541/556) of potential solutions found by experts were also identified by the MATK-assisted analysis. Furthermore, MATK-assisted analysis identified 114 additional potential solutions. The software also showed utility in data reanalysis after remapping to the GRCh38 genome build. Conclusion: MATK expedites the process of identifying likely solving variants in Mendelian traits and helps to remove variability coming from human error and researcher bias. MATK facilitates data re-analysis to keep up with the constantly improving annotation sources and NGS processing pipelines. The software is open source and available at https://gitlab.partners.org/meei-ogi-bioinformatics/MendelAnalysis

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“…The Rare Exome Variant Ensemble Learner (REVEL; Ioannidis et al, 2016) and Combined Annotation Dependent Depletion (CADD scores; Rentzsch, Witten, Cooper, Shendure, & Kircher, 2019) for all the variants in this study were obtained using Variant Ranker (http:// vsranker.broadinstitute.org/; Du et al, 2019). The impact of each variant on the CALPAIN 3 protein structure was assessed using VarMap web tool (Stephenson, Laskowski, Nightingale, Hurles, & Thornton, 2019).…”

Section: Transcriptional Studymentioning

confidence: 99%

Splicing impact of deep exonic missense variants in CAPN3 explored systematically by minigene functional assay

et al. 2020

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Improving the accuracy of variant interpretation during diagnostic sequencing is a major goal for genomic medicine. To explore an often‐overlooked splicing effect of missense variants, we developed the functional assay (“minigene”) for the majority of exons of CAPN3, the gene responsible for limb girdle muscular dystrophy. By systematically screening 21 missense variants distributed along the gene, we found that eight clinically relevant missense variants located at a certain distance from the exon–intron borders (deep exonic missense variants) disrupted normal splicing of CAPN3 exons. Several recent machine learning‐based computational tools failed to predict splicing impact for the majority of these deep exonic missense variants, highlighting the importance of including variants of this type in the training sets during the future algorithm development. Overall, 24 variants in CAPN3 gene were explored, leading to the change in the American College of Medical Genetics and Genomics classification of seven of them when results of the “minigene” functional assay were considered. Our findings reveal previously unknown splicing impact of several clinically important variants in CAPN3 and draw attention to the existence of deep exonic variants with a disruptive effect on gene splicing that could be overlooked by the current approaches in clinical genetics.

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Variant Score Ranker—a web application for intuitive missense variant prioritization

Cited by 5 publications

References 7 publications

The importance of automation in genetic diagnosis: Lessons from analyzing an inherited retinal degeneration cohort with the Mendelian Analysis Toolkit (MATK)

The importance of automation in genetic diagnosis: Lessons from analyzing an inherited retinal degeneration cohort with the Mendelian Analysis Toolkit (MATK)

The Importance of Automation in Genetic Diagnosis: Lessons from Analyzing an Inherited Retinal Degeneration Cohort with the Mendelian Analysis Toolkit (MATK)

Splicing impact of deep exonic missense variants in CAPN3 explored systematically by minigene functional assay

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