rs1800375

Positions:

• chr12-6065257-T-A

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.1173A>T​(p.Thr391Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 1,613,370 control chromosomes in the GnomAD database, including 24,970 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (5793 hom., cov: 33)
  • Exomes 𝑓: 0.15 (19177 hom.)
• Consequence: VWF NM_000552.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.36

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 12-6065257-T-A is Benign according to our data. Variant chr12-6065257-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 256650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6065257-T-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.36 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.467 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5	c.1173A>T	p.Thr391Thr	synonymous_variant	11/52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.1173A>T	p.Thr391Thr	synonymous_variant	11/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.1173A>T	p.Thr391Thr	synonymous_variant	11/52	1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000538635.5	n.420+45258A>T		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34627 AN: 151850 Hom.: 5777 Cov.: 33

Gnomad AFR AF: 0.472

Gnomad AMI AF: 0.0725

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.0755

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.235

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.186

GnomAD3 exomes AF: 0.162 AC: 40630 AN: 250598 Hom.: 4388 AF XY: 0.163 AC XY: 22036 AN XY: 135502

Gnomad AFR exome AF: 0.464

Gnomad AMR exome AF: 0.0840

Gnomad ASJ exome AF: 0.0914

Gnomad EAS exome AF: 0.228

Gnomad SAS exome AF: 0.240

Gnomad FIN exome AF: 0.107

Gnomad NFE exome AF: 0.129

Gnomad OTH exome AF: 0.144

GnomAD4 exome AF: 0.149 AC: 217122 AN: 1461402 Hom.: 19177 Cov.: 34 AF XY: 0.151 AC XY: 109495 AN XY: 726974

Gnomad4 AFR exome AF: 0.475

Gnomad4 AMR exome AF: 0.0903

Gnomad4 ASJ exome AF: 0.0903

Gnomad4 EAS exome AF: 0.215

Gnomad4 SAS exome AF: 0.240

Gnomad4 FIN exome AF: 0.106

Gnomad4 NFE exome AF: 0.134

Gnomad4 OTH exome AF: 0.167

GnomAD4 genome AF: 0.228 AC: 34693 AN: 151968 Hom.: 5793 Cov.: 33 AF XY: 0.225 AC XY: 16708 AN XY: 74320

Gnomad4 AFR AF: 0.472

Gnomad4 AMR AF: 0.132

Gnomad4 ASJ AF: 0.0755

Gnomad4 EAS AF: 0.221

Gnomad4 SAS AF: 0.235

Gnomad4 FIN AF: 0.103

Gnomad4 NFE AF: 0.133

Gnomad4 OTH AF: 0.186

Alfa AF: 0.157 Hom.: 818

Bravo AF: 0.240

Asia WGS AF: 0.241 AC: 839 AN: 3478

EpiCase AF: 0.129

EpiControl AF: 0.131

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 25, 2020	- -
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	-0.85
CADD	Benign	2.5
DANN	Benign	0.26

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: rs1800375; hg19: chr12-6174423; COSMIC: COSV54614898;