VIP-HL: Semi-automated ACMG/AMP variant interpretation platform for
genetic hearing loss
The American College of Medical Genetics and Genomics, and the
Association for Molecular Pathology (ACMG/AMP) have proposed a set of
evidence-based guidelines to support sequence variant interpretation.
The ClinGen hearing loss expert panel (HL-EP) introduced further
specifications into the ACMG/AMP framework for genetic hearing loss.
This study developed a tool named VIP-HL, aiming to semi-automate the HL
ACMG/AMP rules. VIP-HL aggregates information from external databases to
automate 13 out of 24 ACMG/AMP rules specified by HL-EP, namely PVS1,
PS1, PM1, PM2, PM4, PM5, PP3, BA1, BS1, BS2, BP3, BP4, and BP7. We
benchmarked VIP-HL using 50 variants where 83 rules were activated by
the ClinGen HL-EP. VIP-HL concordantly activated 96% (80/83) rules,
significantly higher than that of by InterVar (47%; 39/83). Of 4948
ClinVar star 2+ variants from 142 deafness-related genes, VIP-HL
achieved an overall variant interpretation concordance in 88.0%
(4353/4948). VIP-HL is an integrated online tool for reliable automated
variant classification in hearing loss genes. It assists curators in
variant interpretation and provides a platform for users to share
classifications with each other. VIP-HL is available with a
user-friendly web interface at http://hearing.genetics.bgi.com/.