rs1053523

Variant names:

• chr12-5985618-T-C
• rs1053523
• NM_000552.5:c.6846A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000552.5(VWF):​c.6846A>G​(p.Thr2282Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 1,613,996 control chromosomes in the GnomAD database, including 17,917 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1862 hom., cov: 33)
  • Exomes 𝑓: 0.14 (16055 hom.)
• Consequence: VWF NM_000552.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:8
• Conservation: PhyloP100: -1.38
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• hereditary von Willebrand disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• von Willebrand disease type 2B

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• von Willebrand disease 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• von Willebrand disease 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• von Willebrand disease type 2A

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• von Willebrand disease type 2M

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• von Willebrand disease 3

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• von Willebrand disease type 2N

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 12-5985618-T-C is Benign according to our data. Variant chr12-5985618-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.38 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5	c.6846A>G	p.Thr2282Thr	synonymous_variant	Exon 39 of 52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.6846A>G	p.Thr2282Thr	synonymous_variant	Exon 39 of 52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.6846A>G	p.Thr2282Thr	synonymous_variant	Exon 39 of 52	1	NM_000552.5	ENSP00000261405.5

Frequencies

GnomAD3 genomes AF: 0.149 AC: 22640 AN: 152134 Hom.: 1863 Cov.: 33

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.134

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.0668

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.145

GnomAD2 exomes AF: 0.117 AC: 29329 AN: 251008 AF XY: 0.114

Gnomad AFR exome AF: 0.197

Gnomad AMR exome AF: 0.0753

Gnomad ASJ exome AF: 0.137

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.107

Gnomad NFE exome AF: 0.150

Gnomad OTH exome AF: 0.126

GnomAD4 exome AF: 0.141 AC: 206671 AN: 1461744 Hom.: 16055 Cov.: 36 AF XY: 0.139 AC XY: 101168 AN XY: 727170

African (AFR) AF: 0.195 AC: 6519 AN: 33480

American (AMR) AF: 0.0787 AC: 3518 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 3615 AN: 26136

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39700

South Asian (SAS) AF: 0.0680 AC: 5868 AN: 86256

European-Finnish (FIN) AF: 0.108 AC: 5739 AN: 53332

Middle Eastern (MID) AF: 0.109 AC: 631 AN: 5768

European-Non Finnish (NFE) AF: 0.155 AC: 172673 AN: 1111958

Other (OTH) AF: 0.134 AC: 8100 AN: 60394

GnomAD4 genome AF: 0.149 AC: 22634 AN: 152252 Hom.: 1862 Cov.: 33 AF XY: 0.143 AC XY: 10679 AN XY: 74442

African (AFR) AF: 0.193 AC: 8033 AN: 41534

American (AMR) AF: 0.131 AC: 2011 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 465 AN: 3472

East Asian (EAS) AF: 0.000965 AC: 5 AN: 5182

South Asian (SAS) AF: 0.0668 AC: 323 AN: 4832

European-Finnish (FIN) AF: 0.103 AC: 1094 AN: 10602

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.151 AC: 10292 AN: 68014

Other (OTH) AF: 0.144 AC: 303 AN: 2110

Alfa AF: 0.152 Hom.: 1123

Bravo AF: 0.152

Asia WGS AF: 0.0450 AC: 161 AN: 3478

EpiCase AF: 0.149

EpiControl AF: 0.153

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1 Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Allele frequency is common in at least one population database (frequency: 19.693% 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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

von Willebrand disease type 2 Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

von Willebrand disease type 3 Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

von Willebrand disease type 1 Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary von Willebrand disease Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.30
DANN	Benign	0.59
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1053523; hg19: chr12-6094784; COSMIC: COSV54636419;