rs560397436

Positions:

• chr12-6022864-G-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.3414C>T​(p.Asn1138=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (207 hom., cov: 13)
  • Exomes 𝑓: 0.064 (1059 hom.)
• Consequence: VWF NM_000552.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.04

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=-0.8).
• BP6: Variant 12-6022864-G-A is Benign according to our data. Variant chr12-6022864-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6022864-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0661 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWF	NM_000552.5	c.3414C>T	p.Asn1138=	synonymous_variant	26/52	ENST00000261405.10
VWF	XM_047429501.1	c.3414C>T	p.Asn1138=	synonymous_variant	26/52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWF	ENST00000261405.10	c.3414C>T	p.Asn1138=	synonymous_variant	26/52	1	NM_000552.5	P1
VWF	ENST00000538635.5	n.421-28930C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0482 AC: 5511 AN: 114326 Hom.: 207 Cov.: 13

Gnomad AFR AF: 0.0106

Gnomad AMI AF: 0.00897

Gnomad AMR AF: 0.0468

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.000461

Gnomad SAS AF: 0.0397

Gnomad FIN AF: 0.0608

Gnomad MID AF: 0.0894

Gnomad NFE AF: 0.0679

Gnomad OTH AF: 0.0496

GnomAD3 exomes AF: 0.0509 AC: 2758 AN: 54170 Hom.: 93 AF XY: 0.0521 AC XY: 1424 AN XY: 27320

Gnomad AFR exome AF: 0.0101

Gnomad AMR exome AF: 0.0496

Gnomad ASJ exome AF: 0.114

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0381

Gnomad FIN exome AF: 0.0992

Gnomad NFE exome AF: 0.0774

Gnomad OTH exome AF: 0.0696

GnomAD4 exome AF: 0.0639 AC: 26989 AN: 422162 Hom.: 1059 Cov.: 3 AF XY: 0.0634 AC XY: 14170 AN XY: 223672

Gnomad4 AFR exome AF: 0.0139

Gnomad4 AMR exome AF: 0.0482

Gnomad4 ASJ exome AF: 0.113

Gnomad4 EAS exome AF: 0.000143

Gnomad4 SAS exome AF: 0.0415

Gnomad4 FIN exome AF: 0.0725

Gnomad4 NFE exome AF: 0.0741

Gnomad4 OTH exome AF: 0.0712

GnomAD4 genome AF: 0.0481 AC: 5505 AN: 114432 Hom.: 207 Cov.: 13 AF XY: 0.0468 AC XY: 2484 AN XY: 53030

Gnomad4 AFR AF: 0.0106

Gnomad4 AMR AF: 0.0466

Gnomad4 ASJ AF: 0.106

Gnomad4 EAS AF: 0.000463

Gnomad4 SAS AF: 0.0401

Gnomad4 FIN AF: 0.0608

Gnomad4 NFE AF: 0.0679

Gnomad4 OTH AF: 0.0476

Alfa AF: 0.0891 Hom.: 38

Bravo AF: 0.0491

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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 Benign:3

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 28, 2022	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
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	-0.80
CADD	Benign	0.10
DANN	Benign	0.67

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: rs560397436; hg19: chr12-6132030; COSMIC: COSV54616284; COSMIC: COSV54616284;