rs61751302

Positions:

chr12-5953542-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BS2_Supporting

The NM_000552.5(VWF):c.7940C>T(p.Thr2647Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00401 in 1,614,124 control chromosomes in the GnomAD database, including 21 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 0.0033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0041 ( 21 hom. )

Consequence

VWF
NM_000552.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.336

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:

VWF (HGNC:):

VWF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

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.

BS2

High AC in GnomAd4 at 507 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.7940C>T	p.Thr2647Met	missense_variant	48/52	ENST00000261405.10	NP_000543.3	P04275-1
VWF	XM_047429501.1 linkuse as main transcript	c.7940C>T	p.Thr2647Met	missense_variant	48/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
VWF	ENST00000261405.10 linkuse as main transcript	c.7940C>T	p.Thr2647Met	missense_variant	48/52	1	NM_000552.5	ENSP00000261405.5	P04275-1
VWF	ENST00000612016.1 linkuse as main transcript	n.349C>T		non_coding_transcript_exon_variant	1/3	5
VWF	ENST00000621700.1 linkuse as main transcript	n.258C>T		non_coding_transcript_exon_variant	3/4	3

Frequencies

GnomAD3 genomes

AF:

0.00333

AC:

507

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0195

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00369

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00351

AC:

883

AN:

251454

Hom.:

AF XY:

0.00361

AC XY:

491

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00198

Gnomad EAS exome

AF:

0.000217

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.0190

Gnomad NFE exome

AF:

0.00353

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00408

AC:

5961

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00399

AC XY:

2899

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.000492

Gnomad4 ASJ exome

AF:

0.00187

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.000209

Gnomad4 FIN exome

AF:

0.0191

Gnomad4 NFE exome

AF:

0.00414

Gnomad4 OTH exome

AF:

0.00363

GnomAD4 genome

AF:

0.00333

AC:

507

AN:

152256

Hom.:

Cov.:

AF XY:

0.00359

AC XY:

267

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.000722

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.0195

Gnomad4 NFE

AF:

0.00369

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00313

Hom.:

Bravo

AF:

0.00193

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00198

AC:

ExAC

AF:

0.00274

AC:

333

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00349

EpiControl

AF:

0.00261

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:3Other:1

not provided, no classification provided	literature only	Academic Unit of Haematology, University of Sheffield	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2017	The T2647M variant in the VWF gene has been reported previously in individuals with VWF type 1 and in healthy controls (Bellissimo et al., 2012; James et al., 2007a; James et al., 2007b). The T2647M variant is observed in 112/6614 (1.7%) alleles from individuals of Finnish European background including multiple unrelated homozygous individuals in the ExAC dataset, which is greater than expected for this disorder (Lek et al., 2016). This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. However, the T2647M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties.We interpret T2647M as a variant of uncertain significance. -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 16, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 28, 2023	- -

von Willebrand disease type 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	research	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 30, 2023	- -

Hereditary von Willebrand disease

Uncertain:2

Uncertain significance, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Feb 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Sep 10, 2019	- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

von Willebrand disease type 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

- -

VWF-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 28, 2024

The VWF c.7940C>T variant is predicted to result in the amino acid substitution p.Thr2647Met. This variant was reported in multiple individuals with Von Willebrand disease 1 (For example see: James et al. 2007. PubMed ID: 17190853; Bellissimo et al. 2011. PubMed ID: 22197721; Manderstedt et al. 2019. PubMed ID: 31026269). This variant is reported in 2.0% of alleles in individuals of European (Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Oct 21, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.53

CADD

Benign

2.1

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.76

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.73

MetaRNN

Benign

0.0062

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.3

PrimateAI

Benign

0.23

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.11

Sift

Benign

0.097

Sift4G

Benign

0.090

Polyphen

0.0030

Vest4

0.18

MVP

0.45

MPC

0.91

ClinPred

0.015

GERP RS

-3.8

Varity_R

0.034

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.28

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.28

Position offset: -46

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