rs1555198442
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_000552.5(VWF):c.1562_1563delGCinsCT(p.Cys521Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 31)
Consequence
VWF
NM_000552.5 missense
NM_000552.5 missense
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.36
Genes affected
VWF (HGNC:12726): (von Willebrand factor) This gene encodes a glycoprotein involved in hemostasis. The encoded preproprotein is proteolytically processed following assembly into large multimeric complexes. These complexes function in the adhesion of platelets to sites of vascular injury and the transport of various proteins in the blood. Mutations in this gene result in von Willebrand disease, an inherited bleeding disorder. An unprocessed pseudogene has been found on chromosome 22. [provided by RefSeq, Oct 2015]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), VWF. . Gene score misZ 0.98969 (greater than the threshold 3.09). Trascript score misZ 3.5064 (greater than threshold 3.09). GenCC has associacion of gene with von Willebrand disease type 2M, hereditary von Willebrand disease, von Willebrand disease type 2B, von Willebrand disease type 2N, von Willebrand disease 2, von Willebrand disease type 2A, von Willebrand disease 3, von Willebrand disease 1.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
VWF | NM_000552.5 | c.1562_1563delGCinsCT | p.Cys521Ser | missense_variant | ENST00000261405.10 | NP_000543.3 | ||
VWF | XM_047429501.1 | c.1562_1563delGCinsCT | p.Cys521Ser | missense_variant | XP_047285457.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
VWF | ENST00000261405.10 | c.1562_1563delGCinsCT | p.Cys521Ser | missense_variant | 1 | NM_000552.5 | ENSP00000261405.5 | |||
VWF | ENST00000538635.5 | n.420+52499_420+52500delGCinsCT | intron_variant | 4 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 31
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 10, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 26, 2024 | The VWF c.1562_1563delinsCT (p.Cys521Ser) variant has not been reported in individuals with VWF-related conditions in the published literature. The frequency of this variant in the general population, 0.0045 (109/24426 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 22, 2024 | Variant summary: VWF c.1562_1563delinsCT (p.Cys521Ser) results in a non-conservative amino acid change located in the von Willebrand factor, type D domain (IPR001846) of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 1613320 control chromosomes in the gnomAD database, including 1 homozygotes. To our knowledge, no occurrence of c.1562_1563delinsCT in individuals affected with Von Willebrand Disease and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 439322). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
von Willebrand disease type 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Jun 22, 2023 | This VWF missense variant (rs1555198442) has an entry in ClinVar (Variation ID: 439322), but has not been reported in the literature in individuals with VWF-related conditions. It has been identified in a large population dataset and the minor allele frequency is neither low enough to consider the variant rare (<0.1%) nor high enough to consider it a population polymorphism (>1%) within the African/African American subpopulation (gnomADv2.1.1: 109/24426 alleles; 0.4462 %, no homozygotes). Of two bioinformatics tools queried, one predicts that the substitution would be damaging, while one predicts that it would be tolerated. The cystine residue at this position is conserved across all species assessed except for one that has a serine at this position. We consider the clinical significance of VWF c.1562_1563delinsCT to be uncertain at this time. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at