rs1555198442

Positions:

• chr12-6058015-GC-AG

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The ENST00000261405.10(VWF):​c.1562_1563delinsCT​(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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Synonymous variant affecting the same amino acid position (i.e. C521C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: VWF ENST00000261405.10 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• 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]

ACMG classification

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_1563delinsCT	p.Cys521Ser	missense_variant	14/52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.1562_1563delinsCT	p.Cys521Ser	missense_variant	14/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.1562_1563delinsCT	p.Cys521Ser	missense_variant	14/52	1	NM_000552.5	ENSP00000261405	P1
VWF	ENST00000538635.5	n.420+52499_420+52500delinsCT		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

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	Jun 20, 2023	To the best of our knowledge, this variant has not been reported 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: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555198442; hg19: chr12-6167181;