chr12-6019004-C-G
Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1
The NM_000552.5(VWF):c.4414G>C(p.Asp1472His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,613,312 control chromosomes in the GnomAD database, including 17,108 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1472P?) has been classified as Uncertain significance.
Frequency
Consequence
NM_000552.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VWF | NM_000552.5 | c.4414G>C | p.Asp1472His | missense_variant | 28/52 | ENST00000261405.10 | |
VWF | XM_047429501.1 | c.4414G>C | p.Asp1472His | missense_variant | 28/52 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VWF | ENST00000261405.10 | c.4414G>C | p.Asp1472His | missense_variant | 28/52 | 1 | NM_000552.5 | P1 | |
VWF | ENST00000538635.5 | n.421-25070G>C | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.208 AC: 31589AN: 151844Hom.: 5730 Cov.: 31
GnomAD3 exomes AF: 0.119 AC: 29448AN: 248378Hom.: 3144 AF XY: 0.116 AC XY: 15611AN XY: 134782
GnomAD4 exome AF: 0.104 AC: 152489AN: 1461350Hom.: 11370 Cov.: 99 AF XY: 0.104 AC XY: 75805AN XY: 726966
GnomAD4 genome ? AF: 0.208 AC: 31629AN: 151962Hom.: 5738 Cov.: 31 AF XY: 0.205 AC XY: 15247AN XY: 74276
ClinVar
Submissions by phenotype
not specified Benign:3
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 29, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 20, 2023 | - - |
von Willebrand disease type 2 Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Dec 05, 2021 | - - |
von Willebrand disease type 2M Benign:1
Benign, criteria provided, single submitter | clinical testing | Versiti Diagnostic Laboratories, Versiti, Inc | Aug 04, 2017 | The missense variant c.4414G>C in exon 28 of the VWF gene changes aspartic acid at codon 1472 to histidine (p.D1472H). The p.D1472H variant is common in the general population (12%, Exome Aggregation Consortium) and frequently found in individuals of African descent (50%, Exome Aggregation Consortium). Although the p.D1472H variant is not thought to cause type 1 or 2M von Willebrand disease (Flood, 2010), individuals who are heterozygous or homozygous for p.D1472H may exhibit reduced ratio of VWF ristocetin cofactor activity to VWF antigen. However, p.D1472H does not have physiological consequences; specifically it does not affect VWF multimer distribution or ristocetin-independent binding of VWF to GP1b complex, and does not result in increased risk for bleeding. In summary, VWF c.4414G>C, p.D1472H, is a benign variant with respect to von Willebrand disease. - |
von Willebrand disease type 3 Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Dec 05, 2021 | - - |
von Willebrand disease type 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Dec 05, 2021 | - - |
Hereditary von Willebrand disease Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at