rs33978901

Variant names:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 5P and 12B. PM1PM5PP2BP4_StrongBS1BS2

The NM_000552.5(VWF):c.2771G>A(p.Arg924Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0177 in 1,614,096 control chromosomes in the GnomAD database, including 297 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R924W) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.012 ( 13 hom., cov: 31)

Exomes 𝑓: 0.018 ( 284 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:9O:1

Conservation

PhyloP100: 0.511

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 Benign. Variant got -7 ACMG points.

PM1

In a disulfide_bond (size 142) in uniprot entity VWF_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_000552.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-6031494-G-A is described in Lovd as [Likely_pathogenic].

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=0.00859642).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0118 (1799/152226) while in subpopulation NFE AF= 0.0202 (1374/68008). AF 95% confidence interval is 0.0193. There are 13 homozygotes in gnomad4. There are 816 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1799 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5 link	c.2771G>A	p.Arg924Gln	missense_variant	Exon 21 of 52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 link	c.2771G>A	p.Arg924Gln	missense_variant	Exon 21 of 52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10 link	c.2771G>A	p.Arg924Gln	missense_variant	Exon 21 of 52	1	NM_000552.5	ENSP00000261405.5		P04275-1
VWF	ENST00000538635.5 link	n.421-37559G>A		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes

AF:

0.0118

AC:

1799

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00370

Gnomad AMI

AF:

0.0176

Gnomad AMR

AF:

0.0102

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00517

Gnomad FIN

AF:

0.00509

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0202

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.0105

AC:

2647

AN:

251494

Hom.:

AF XY:

0.0107

AC XY:

1449

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.00252

Gnomad AMR exome

AF:

0.00448

Gnomad ASJ exome

AF:

0.00298

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00366

Gnomad FIN exome

AF:

0.00550

Gnomad NFE exome

AF:

0.0186

Gnomad OTH exome

AF:

0.0112

GnomAD4 exome

AF:

0.0184

AC:

26843

AN:

1461870

Hom.:

284

Cov.:

AF XY:

0.0178

AC XY:

12950

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00293

Gnomad4 AMR exome

AF:

0.00425

Gnomad4 ASJ exome

AF:

0.00329

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00351

Gnomad4 FIN exome

AF:

0.00620

Gnomad4 NFE exome

AF:

0.0224

Gnomad4 OTH exome

AF:

0.0153

GnomAD4 genome

AF:

0.0118

AC:

1799

AN:

152226

Hom.:

Cov.:

AF XY:

0.0110

AC XY:

816

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00368

Gnomad4 AMR

AF:

0.0101

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00518

Gnomad4 FIN

AF:

0.00509

Gnomad4 NFE

AF:

0.0202

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.0172

Hom.:

Bravo

AF:

0.0112

TwinsUK

AF:

0.0194

AC:

ALSPAC

AF:

0.0226

AC:

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.0212

AC:

182

ExAC

AF:

0.0106

AC:

1290

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0192

EpiControl

AF:

0.0159

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:9Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4Other:1

Oct 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

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

- -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

VWF: BP4, BS1, BS2 -

Feb 03, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 29, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

von Willebrand disease type 2

Uncertain:1Benign:2

Apr 26, 2022

Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 06, 2022

Laboratory of Hematology, Radboud University Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

von Willebrand disease type 1

Uncertain:1Benign:1

May 06, 2022

Laboratory of Hematology, Radboud University Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

von Willebrand disease type 3

Benign:2

Nov 01, 2020

Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

ClinGen Pathogenicity Calculator -

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary von Willebrand disease

Uncertain:1

Dec 13, 2019

Genetics and Molecular Pathology, SA Pathology

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

0.070

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.24

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.85

MetaRNN

Benign

0.0086

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.49

REVEL

Benign

0.089

Sift

Benign

0.16

Sift4G

Benign

0.15

Polyphen

0.023

Vest4

0.13

MPC

0.24

ClinPred

0.0062

GERP RS

3.8

Varity_R

0.088

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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