12-6019394-G-A

Position:

chr12-6019394-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PP2PP3BS2_Supporting

The NM_000552.5(VWF):c.4024C>T(p.Arg1342Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000057 in 1,613,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3O:1

Conservation

PhyloP100: 4.37

Variant links:

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]

VWF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1

In a disulfide_bond (size 186) in uniprot entity VWF_HUMAN there are 58 pathogenic changes around while only 4 benign (94%) in NM_000552.5

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.832

BS2

High AC in GnomAd4 at 23 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5 linkuse as main transcript	c.4024C>T	p.Arg1342Cys	missense_variant	28/52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1 linkuse as main transcript	c.4024C>T	p.Arg1342Cys	missense_variant	28/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 linkuse as main transcript	c.4024C>T	p.Arg1342Cys	missense_variant	28/52	1	NM_000552.5	ENSP00000261405	P1	P04275-1
VWF	ENST00000538635.5 linkuse as main transcript	n.421-25460C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000116

AC:

AN:

250684

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135612

show subpopulations

Gnomad AFR exome

AF:

0.000988

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000472

AC:

AN:

1461628

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

727130

show subpopulations

Gnomad4 AFR exome

AF:

0.00120

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000151

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.000529

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000280

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000157

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 03, 2023	The frequency of this variant in the general population, 0.0008 (20/24896 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals/families with Type I (PMID: 19453940 (2010)) or Type 2 von Willebrand disease (vWD) (PMIDs: 27443694 (2016), 19506361 (2009), 19298374 (2009), 18315556 (2008), 16985174 (2007), and 16321553 (2006)). In addition, this variant has been reported in healthy control individuals (PMIDs: 33556167 (2021) and 22197721 (2012)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
not provided, no classification provided	literature only	Academic Unit of Haematology, University of Sheffield	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 14, 2023	The VWF c.4024C>T; p.Arg1342Cys variant (rs61749404) is reported in the literature in individuals affected with von Willebrand disease type 1 (Goodeve 2007), but has also been found in healthy controls (Bellissimo 2012, Sadler 2021). This variant is reported in ClinVar (Variation ID: 100616) and is found in the African/African-American population with an allele frequency of 0.08% (20/24,896 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.907). Due to conflicting information, the clinical significance of this variant is uncertain at this time. References: Bellissimo DB et al. VWF mutations and new sequence variations identified in healthy controls are more frequent in the African-American population. Blood. 2012 Mar 1;119(9):2135-40. PMID: 22197721. Goodeve A et al. Phenotype and genotype of a cohort of families historically diagnosed with type 1 von Willebrand disease in the European study, Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease (MCMDM-1VWD). Blood. 2007 Jan 1;109(1):112-21. PMID: 16985174. Sadler B et al. von Willebrand factor antigen levels are associated with burden of rare nonsynonymous variants in the VWF gene. Blood. 2021 Jun 10;137(23):3277-3283. PMID: 33556167. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 30, 2024

Variant summary: VWF c.4024C>T (p.Arg1342Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 250684 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in VWF causing Von Willebrand Disease, allowing no conclusion about variant significance. c.4024C>T has been reported in the literature in individuals affected with Von Willebrand Disease without strong evidence of causality (e.g. Kakela_2006, Goodeve_2007). These reports do not provide unequivocal conclusions about association of the variant with Von Willebrand Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 16985174, 16321553, 19298374). ClinVar contains an entry for this variant (Variation ID: 100616). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.66

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.83

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.1

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.84

MVP

0.94

MPC

1.1

ClinPred

0.48

GERP RS

5.0

Varity_R

0.56

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over