rs61750595

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000552.5(VWF):c.4975C>T(p.Arg1659Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,612,998 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

VWF
NM_000552.5 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8O:2

Conservation

PhyloP100: 1.07

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 Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 12-6018443-G-A is Pathogenic according to our data. Variant chr12-6018443-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6018443-G-A is described in Lovd as [Likely_pathogenic]. Variant chr12-6018443-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5 linkuse as main transcript	c.4975C>T	p.Arg1659Ter	stop_gained	28/52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1 linkuse as main transcript	c.4975C>T	p.Arg1659Ter	stop_gained	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.4975C>T	p.Arg1659Ter	stop_gained	28/52	1	NM_000552.5	ENSP00000261405	P1	P04275-1
VWF	ENST00000538635.5 linkuse as main transcript	n.421-24509C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000559

AC:

AN:

250392

Hom.:

AF XY:

0.0000665

AC XY:

AN XY:

135374

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000372

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.0000335

AC:

AN:

1460882

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

726644

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000620

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0725

Hom.:

708

Bravo

AF:

0.0000113

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 15, 2019	This nonsense variant causes the premature termination of VWF protein synthesis. In addition, it has been reported in individuals affected with VWD Type 3 in the published literature (PMID: 20147343 (2010), 24712919 (2014), 18485763 (2008), 23834637 (2013), 28971901 (2017), 24675615 (2014)). Therefore, the variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 02, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 35505650, 31050121, 25525159, 1301136, 31589614, 29423401, 23834637, 9845532, 24712919, 18485763, 20147343) -
not provided, no classification provided	literature only	Academic Unit of Haematology, University of Sheffield	-	- -

von Willebrand disease type 3

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico	Nov 01, 2020	variant already reported in ClinVar -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1992	- -

von Willebrand disease type 1

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1992	- -

Hereditary von Willebrand disease

Pathogenic:1Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 19, 2022	Variant summary: VWF c.4975C>T (p.Arg1659X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 5.6e-05 in 250392 control chromosomes. This frequency does not allow conclusions about variant significance. c.4975C>T has been reported in the literature as a homozygous or compound heterozygous genotype in multiple individuals affected with Von Willebrand Disease type 3 (example, Mohl_2011, Lapi_2022, Zhang_1992, Ahmad_2014). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -

VWF-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 17, 2024

The VWF c.4975C>T variant is predicted to result in premature protein termination (p.Arg1659*). This variant has been well documented to be pathogenic for autosomal recessive Von Willebrand disease 3 (Ahmad et al. 2014. PubMed ID: 24712919; Borràs et al. 2017. PubMed ID: 28971901. Table S4; Gupta et al. 2008. PubMed ID: 18485763). This variant is reported in 0.040% of alleles in individuals of European (Finnish) descent in gnomAD. Nonsense variants in VWF are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.43

Eigen_PC

Benign

0.22

FATHMM_MKL

Benign

0.44

MutationTaster

Benign

1.0

Vest4

0.72

GERP RS

3.0

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