rs216310

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000552.5(VWF):c.4641T>C(p.Thr1547=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 1,601,608 control chromosomes in the GnomAD database, including 341,539 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.72 ( 39994 hom., cov: 30)

Exomes 𝑓: 0.64 ( 301545 hom. )

Consequence

VWF
NM_000552.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:13

Conservation

PhyloP100: -1.16

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.99).

BP6

Variant 12-6018777-A-G is Benign according to our data. Variant chr12-6018777-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 256680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6018777-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.16 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.885 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5 linkuse as main transcript	c.4641T>C	p.Thr1547=	synonymous_variant	28/52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1 linkuse as main transcript	c.4641T>C	p.Thr1547=	synonymous_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.4641T>C	p.Thr1547=	synonymous_variant	28/52	1	NM_000552.5	ENSP00000261405	P1	P04275-1
VWF	ENST00000538635.5 linkuse as main transcript	n.421-24843T>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.716

AC:

108540

AN:

151694

Hom.:

39958

Cov.:

show subpopulations

Gnomad AFR

AF:

0.893

Gnomad AMI

AF:

0.688

Gnomad AMR

AF:

0.753

Gnomad ASJ

AF:

0.689

Gnomad EAS

AF:

0.748

Gnomad SAS

AF:

0.773

Gnomad FIN

AF:

0.546

Gnomad MID

AF:

0.772

Gnomad NFE

AF:

0.620

Gnomad OTH

AF:

0.723

GnomAD3 exomes

AF:

0.689

AC:

169960

AN:

246712

Hom.:

60268

AF XY:

0.685

AC XY:

91410

AN XY:

133488

show subpopulations

Gnomad AFR exome

AF:

0.902

Gnomad AMR exome

AF:

0.807

Gnomad ASJ exome

AF:

0.687

Gnomad EAS exome

AF:

0.764

Gnomad SAS exome

AF:

0.757

Gnomad FIN exome

AF:

0.548

Gnomad NFE exome

AF:

0.619

Gnomad OTH exome

AF:

0.678

GnomAD4 exome

AF:

0.639

AC:

926963

AN:

1449796

Hom.:

301545

Cov.:

AF XY:

0.642

AC XY:

462459

AN XY:

720526

show subpopulations

Gnomad4 AFR exome

AF:

0.905

Gnomad4 AMR exome

AF:

0.802

Gnomad4 ASJ exome

AF:

0.689

Gnomad4 EAS exome

AF:

0.738

Gnomad4 SAS exome

AF:

0.751

Gnomad4 FIN exome

AF:

0.547

Gnomad4 NFE exome

AF:

0.614

Gnomad4 OTH exome

AF:

0.667

GnomAD4 genome

AF:

0.716

AC:

108630

AN:

151812

Hom.:

39994

Cov.:

AF XY:

0.718

AC XY:

53229

AN XY:

74160

show subpopulations

Gnomad4 AFR

AF:

0.892

Gnomad4 AMR

AF:

0.753

Gnomad4 ASJ

AF:

0.689

Gnomad4 EAS

AF:

0.748

Gnomad4 SAS

AF:

0.773

Gnomad4 FIN

AF:

0.546

Gnomad4 NFE

AF:

0.620

Gnomad4 OTH

AF:

0.719

Alfa

AF:

0.647

Hom.:

9534

Bravo

AF:

0.739

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:5

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	Allele frequency is common in at least one population database (frequency: 90.157% in gnomAD_Exomes) based on the frequency threshold of 0.5% for this gene. Variant was observed in a homozygous state in population databases more than expected for disease. A synonymous variant not located in a splice region. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 17, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 13, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 10, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 03, 2020	The p.Thr1547Thr variant in VWF is classified as benign because it does not alter an amino acid residue, is not located within the splice consensus site, and computational splice prediction tools do not predict an impact on splicing. It has been identified in 90% (22058/24566) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1, BP4, BP7. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

von Willebrand disease type 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

von Willebrand disease type 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

von Willebrand disease type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Hereditary von Willebrand disease

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.99

CADD

Benign

0.071

DANN

Benign

0.28

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