AutoPVS1: An automatic classification tool for PVS1 interpretation of null variants

Abstract

Null variants are prevalent within the human genome, and their accurate interpretation is critical for clinical management. In 2018, the ClinGen Sequence Variant Interpretation (SVI) Working Group refined the only criterion with a very strong pathogenicity rating (PVS1). To streamline PVS1 interpretation, we have developed an automatic classification tool with a graphical user interface called AutoPVS1. The performance of AutoPVS1 was assessed using 56 variants manually curated by the ClinGen's SVI Working Group; it achieved an interpretation concordance of 93% (52/56). A further analysis of 28,586 putative loss‐of‐function variants by AutoPVS1 demonstrated that at least 27.7% of them do not reach a very strong strength level, 17.5% because of variant‐specific issues and 10.2% due to disease mechanism considerations. Notably, 41.0% (1,936/4,717) of splicing variants were assigned a decreased preliminary PVS1 strength level, a significantly greater fraction than in frameshift variants (13.2%) and nonsense variants (10.8%). Our results reinforce the necessity of considering variant‐specific issues and disease mechanisms in variant interpretation and demonstrate that AutoPVS1 meets an urgent need by enabling biocurators to easily assign accurate, reliable and reproducible PVS1 strength levels in the process of variant interpretation. AutoPVS1 is publicly available at http://autopvs1.genetics.bgi.com/.

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

“…ClinGen HL-EP did not perform a systematic review of mutational hot spots or functional domains for all genes associated with hearing loss, and proposed that PM1 can be applied for KCNQ4 pore-forming region. 7 In this study, we used the enrichment of pathogenic/likely pathogenic variants to construct a set of important regions 19 which includes the KCNQ4 pore-forming region. Additionally, although HL-EP did not elaborate on the cutoff for BS2, we used a conservative cutoff to automate this rule.…”

“…clarified before. 19,20 PM1 can be applied when a variant is in a mutational hotspot region or well-studied functional domain without benign variation. 5,7 The hotspot region/domain was determined based on the enrichment of pathogenic variants, as clarified in our recent work.…”

“…5,7 The hotspot region/domain was determined based on the enrichment of pathogenic variants, as clarified in our recent work. 19 Pathogenic/likely pathogenic variants from ClinVar 20200629 release were retrieved to determine the existence of the same amino acid changes (PS1) and the different amino acid changes (PM5). For example, knowing that NM_004004.6(GJB2):c.109G>A (p.Val37Ile) is a well-established pathogenic variant in ClinVar, we can now apply PM5 for NM_004004.6(GJB2):c.109G>T (p.Val37Phe).…”

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

“…The parameterization of nine computational criteria (PVS1, PS1, PM1, PM4, PM5, PP3, BP3, BP4, and BP7) was described as follows. The specifications of PVS1 were clarified before (Abou Tayoun et al, 2018;Xiang, Peng, Baxter, & Peng, 2020). PM1 can be applied when a variant is in a mutational hotspot region or well-studied functional domain without benign variation (Oza et al, 2018;Richards et al, 2015).…”

“…PM1 can be applied when a variant is in a mutational hotspot region or well-studied functional domain without benign variation (Oza et al, 2018;Richards et al, 2015). The hotspot region was determined based on the enrichment of pathogenic variants, as clarified in our recent work (Xiang, Peng, et al, 2020). Pathogenic/likely pathogenic variants from ClinVar 20200629 release were retrieved to determine the existence of the same amino acid changes (PS1) and the different amino acid changes (PM5).…”