rs1053523

Positions:

• chr12-5985618-T-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 256694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-5985618-T-C is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
VWF	NM_000552.5	c.6846A>G	p.Thr2282Thr	synonymous_variant	39/52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.6846A>G	p.Thr2282Thr	synonymous_variant	39/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.6846A>G	p.Thr2282Thr	synonymous_variant	39/52	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

GnomAD3 exomes AF: 0.117 AC: 29329 AN: 251008 Hom.: 2137 AF XY: 0.114 AC XY: 15521 AN XY: 135670

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 SAS exome AF: 0.0678

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

Gnomad4 AFR exome AF: 0.195

Gnomad4 AMR exome AF: 0.0787

Gnomad4 ASJ exome AF: 0.138

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0680

Gnomad4 FIN exome AF: 0.108

Gnomad4 NFE exome AF: 0.155

Gnomad4 OTH exome AF: 0.134

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

Gnomad4 AFR AF: 0.193

Gnomad4 AMR AF: 0.131

Gnomad4 ASJ AF: 0.134

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.0668

Gnomad4 FIN AF: 0.103

Gnomad4 NFE AF: 0.151

Gnomad4 OTH AF: 0.144

Alfa AF: 0.152 Hom.: 848

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

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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Uncertain:1 Benign:1

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: 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. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	-0.65
CADD	Benign	0.30
DANN	Benign	0.59

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

Other links and lift over

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