12-6056880-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 1P and 3B. PP2BP4_ModerateBS2_Supporting

The NM_000552.5(VWF):c.1922C>T(p.Ala641Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,482,824 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00091 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0015 ( 1 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:8O:1

Conservation

PhyloP100: -0.115

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 was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PP2

Missense variant in the VWF gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 149 curated pathogenic missense variants (we use a threshold of 10). The gene has 28 curated benign missense variants. Gene score misZ: 0.98969 (below the threshold of 3.09). Trascript score misZ: 3.5064 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.104133815).

BS2

High AC in GnomAd4 at 139 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 rank	MANE	Protein	UniProt
VWF	NM_000552.5 link	c.1922C>T	p.Ala641Val	missense_variant	Exon 15 of 52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 link	c.1922C>T	p.Ala641Val	missense_variant	Exon 15 of 52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 link	c.1922C>T	p.Ala641Val	missense_variant	Exon 15 of 52	1	NM_000552.5	ENSP00000261405.5		P04275-1
VWF	ENST00000538635.5 link	n.420+53635C>T		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes

AF:

0.000913

AC:

139

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00185

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00102

AC:

AN:

84122

AF XY:

0.00100

show subpopulations

Gnomad AFR exome

AF:

0.00115

Gnomad AMR exome

AF:

0.000248

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00237

Gnomad OTH exome

AF:

0.000376

GnomAD4 exome

AF:

0.00146

AC:

1936

AN:

1330508

Hom.:

Cov.:

AF XY:

0.00141

AC XY:

925

AN XY:

654644

show subpopulations

Gnomad4 AFR exome

AF:

0.000111

AC:

AN:

27112

Gnomad4 AMR exome

AF:

0.000145

AC:

AN:

27596

Gnomad4 ASJ exome

AF:

0.0000449

AC:

AN:

22264

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

32380

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

70884

Gnomad4 FIN exome

AF:

0.000153

AC:

AN:

32766

Gnomad4 NFE exome

AF:

0.00173

AC:

1830

AN:

1057988

Gnomad4 Remaining exome

AF:

0.00168

AC:

AN:

55504

Heterozygous variant carriers

112

224

336

448

560

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

144

216

288

360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000913

AC:

139

AN:

152316

Hom.:

Cov.:

AF XY:

0.000765

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.000192

AC:

0.000192428

AN:

0.000192428

Gnomad4 AMR

AF:

0.000196

AC:

0.000196053

AN:

0.000196053

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.000188

AC:

0.000188324

AN:

0.000188324

Gnomad4 NFE

AF:

0.00185

AC:

0.00185229

AN:

0.00185229

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00150

Hom.:

Bravo

AF:

0.000842

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00148

AC:

ESP6500EA

AF:

0.000750

AC:

ExAC

AF:

0.000257

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:8Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Other:1

Jun 11, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Academic Unit of Haematology, University of Sheffield

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Apr 23, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported as heterozygous in a patient with coagulation disease from the published literature; however this patient also harbored a variant in the F11 gene (PMID: 31064749); Reported in the heterozygous state in an individual with type 1 von Willebrand disease; however, this individual had normal multimers, and incomplete cosegregation of the A641V variant with von Willebrand disease in the family was reported (PMID: 16985174, 18230755); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27734074, 22995991, 19506353, 18344424, 18230755, 33556167, 16985174, 31064749) -

Dec 11, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The VWF c.1922C>T (p.Ala641Val) variant has been reported in the published literature in individuals with Type 1 von Willebrand disease (vWD) (PMIDs: 18344424 (2008), 18230755 (2008), 16985174 (2007)). The frequency of this variant in the general population, 0.0024 (117/48744 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 predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

not specified

Uncertain:2

May 09, 2024

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: VWF c.1922C>T (p.Ala641Val) results in a non-conservative amino acid change located in the VWF/SSPO/Zonadhesin-like, cysteine-rich domain (IPR014853) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.001 in 84122 control chromosomes. c.1922C>T has been reported in the literature in individuals affected with Von Willebrand Disease (example, Downes_2019, Goodeve_2007, Sadler_2021). These report(s) 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: 31064749, 16985174, 33556167). ClinVar contains an entry for this variant (Variation ID: 100196). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

von Willebrand disease type 1;C1264040:von Willebrand disease type 2;C1264041:von Willebrand disease type 3

Uncertain:2

Aug 28, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Feb 09, 2016

Division of Human Genetics, Children's Hospital of Philadelphia

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Hereditary von Willebrand disease

Pathogenic:1

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Hemorrhage

Uncertain:1

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.77

M_CAP

Pathogenic

0.67

MetaRNN

Benign

0.10

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

1.9

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-2.4

REVEL

Uncertain

0.59

Sift

Benign

0.053

Sift4G

Benign

0.084

Polyphen

0.97

Vest4

0.68

MVP

0.73

MPC

0.32

ClinPred

0.066

GERP RS

-5.9

Varity_R

0.079

gMVP

0.39

Mutation Taster

=93/7

disease causing (ClinVar)

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