12-6110515-C-T
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS1
This summary comes from the ClinGen Evidence Repository: NM_000552.5:c.391G>A is a missense variant in VWF that replaces glycine with serine at position 131. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.02093 (based on 1636/75004 alleles in the African/African-American population), which is higher than the ClinGen VWD VCEP threshold (>0.01) for BS1, and therefore meets this criterion (BS1). This variant has been reported in the heterozygous state in at least 5 reported healthy control individuals with no bleeding history and normal lab values (PMID:22197721). However, BS2 has not been considered since this code is not applicable to the gene-disease relationship due to incomplete penetrance. The computational predictor REVEL gives a score of 0.141, which is below the ClinGen VWD VCEP threshold of <0.290 and does not predict a damaging effect on VWF function (BP4). Additionally, the computational splicing predictor SpliceAI indicated that the variant has no impact on splicing. In summary, this variant meets the criteria to be classified as a variant of unknown significance for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BS1, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6403810/MONDO:0019565/090
Frequency
Consequence
NM_000552.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VWF | NM_000552.5 | c.391G>A | p.Gly131Ser | missense_variant | 5/52 | ENST00000261405.10 | |
VWF | XM_047429501.1 | c.391G>A | p.Gly131Ser | missense_variant | 5/52 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VWF | ENST00000261405.10 | c.391G>A | p.Gly131Ser | missense_variant | 5/52 | 1 | NM_000552.5 | P1 | |
VWF | ENST00000321023.5 | c.*450G>A | 3_prime_UTR_variant, NMD_transcript_variant | 6/7 | 1 | ||||
VWF | ENST00000538635.5 | n.420G>A | splice_region_variant, non_coding_transcript_exon_variant | 5/6 | 4 |
Frequencies
GnomAD3 genomes AF: 0.00603 AC: 918AN: 152130Hom.: 10 Cov.: 32
GnomAD3 exomes AF: 0.00187 AC: 470AN: 251492Hom.: 6 AF XY: 0.00148 AC XY: 201AN XY: 135922
GnomAD4 exome AF: 0.000971 AC: 1419AN: 1461892Hom.: 13 Cov.: 31 AF XY: 0.000903 AC XY: 657AN XY: 727246
GnomAD4 genome AF: 0.00606 AC: 922AN: 152248Hom.: 10 Cov.: 32 AF XY: 0.00555 AC XY: 413AN XY: 74446
ClinVar
Submissions by phenotype
not provided Benign:4
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2023 | VWF: BP4, BS1, BS2 - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 28, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 06, 2021 | See Variant Classification Assertion Criteria. - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 20, 2022 | - - |
Hereditary von Willebrand disease Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
von Willebrand disease type 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Nov 07, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at