rs4021576

Positions:

• chr12-6023770-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000261405.10(VWF):​c.3240T>C​(p.Tyr1080=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 1,605,166 control chromosomes in the GnomAD database, including 3,351 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.091 (2069 hom., cov: 31)
  • Exomes 𝑓: 0.0047 (1282 hom.)
• Consequence: VWF ENST00000261405.10 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.44

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 12-6023770-A-G is Benign according to our data. Variant chr12-6023770-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 256663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6023770-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.306 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5	c.3240T>C	p.Tyr1080=	synonymous_variant	25/52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.3240T>C	p.Tyr1080=	synonymous_variant	25/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.3240T>C	p.Tyr1080=	synonymous_variant	25/52	1	NM_000552.5	ENSP00000261405	P1
VWF	ENST00000538635.5	n.421-29836T>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0905 AC: 13760 AN: 152070 Hom.: 2067 Cov.: 31

Gnomad AFR AF: 0.311

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0402

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00153

Gnomad OTH AF: 0.0813

GnomAD3 exomes AF: 0.00979 AC: 2408 AN: 245854 Hom.: 389 AF XY: 0.00781 AC XY: 1042 AN XY: 133492

Gnomad AFR exome AF: 0.162

Gnomad AMR exome AF: 0.00804

Gnomad ASJ exome AF: 0.00100

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000657

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000443

Gnomad OTH exome AF: 0.00564

GnomAD4 exome AF: 0.00472 AC: 6858 AN: 1452978 Hom.: 1282 Cov.: 32 AF XY: 0.00413 AC XY: 2985 AN XY: 723406

Gnomad4 AFR exome AF: 0.191

Gnomad4 AMR exome AF: 0.0116

Gnomad4 ASJ exome AF: 0.00169

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000476

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000278

Gnomad4 OTH exome AF: 0.0121

GnomAD4 genome AF: 0.0906 AC: 13789 AN: 152188 Hom.: 2069 Cov.: 31 AF XY: 0.0872 AC XY: 6493 AN XY: 74422

Gnomad4 AFR AF: 0.311

Gnomad4 AMR AF: 0.0401

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00153

Gnomad4 OTH AF: 0.0804

Alfa AF: 0.0399 Hom.: 171

Bravo AF: 0.104

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 22, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 28, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 11, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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	4.8
DANN	Benign	0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4021576; hg19: chr12-6132936;