rs34510401

Positions:

• chr12-6034787-C-A
• chr12-6034787-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Very_Strong BP7 BS2_Supporting

The NM_000552.5(VWF):​c.2586G>T​(p.Val862=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,614,248 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (15 hom.)
• Consequence: VWF NM_000552.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0410

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 12-6034787-C-A is Benign according to our data. Variant chr12-6034787-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 439329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.041 with no splicing effect.
• BS2: High AC in GnomAd4 at 190 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWF	NM_000552.5	c.2586G>T	p.Val862=	synonymous_variant	20/52	ENST00000261405.10
VWF	XM_047429501.1	c.2586G>T	p.Val862=	synonymous_variant	20/52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWF	ENST00000261405.10	c.2586G>T	p.Val862=	synonymous_variant	20/52	1	NM_000552.5	P1
VWF	ENST00000538635.5	n.421-40853G>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00123 AC: 187 AN: 152240 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00579

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000896

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00236 AC: 594 AN: 251486 Hom.: 7 AF XY: 0.00286 AC XY: 389 AN XY: 135922

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.0199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00621

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00107

Gnomad OTH exome AF: 0.00358

GnomAD4 exome AF: 0.00133 AC: 1940 AN: 1461890 Hom.: 15 Cov.: 31 AF XY: 0.00162 AC XY: 1176 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.0193

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00655

Gnomad4 FIN exome AF: 0.000599

Gnomad4 NFE exome AF: 0.000513

Gnomad4 OTH exome AF: 0.00248

GnomAD4 genome AF: 0.00125 AC: 190 AN: 152358 Hom.: 3 Cov.: 33 AF XY: 0.00138 AC XY: 103 AN XY: 74502

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.0184

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00621

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.000911

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00219 Hom.: 2

Bravo AF: 0.00101

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00169

EpiControl AF: 0.00178

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	VWF: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 06, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 22, 2020

- -

VWF-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 06, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	1.5
DANN	Benign	0.68

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: rs34510401; hg19: chr12-6143953;