rs144796763

Positions:

• chr12-6018975-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Very_Strong BP7 BS2_Supporting

The NM_000552.5(VWF):​c.4443G>T​(p.Gly1481=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,613,908 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0017 (7 hom.)
• Consequence: VWF NM_000552.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.269

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 12-6018975-C-A is Benign according to our data. Variant chr12-6018975-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 440407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6018975-C-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.269 with no splicing effect.
• BS2: High AC in GnomAd4 at 154 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.4443G>T	p.Gly1481=	synonymous_variant	28/52	ENST00000261405.10
VWF	XM_047429501.1	c.4443G>T	p.Gly1481=	synonymous_variant	28/52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWF	ENST00000261405.10	c.4443G>T	p.Gly1481=	synonymous_variant	28/52	1	NM_000552.5	P1
VWF	ENST00000538635.5	n.421-25041G>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 154 AN: 152128 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00194

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00113 AC: 282 AN: 249842 Hom.: 3 AF XY: 0.00120 AC XY: 162 AN XY: 135512

Gnomad AFR exome AF: 0.000324

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00203

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00177

Gnomad OTH exome AF: 0.000494

GnomAD4 exome AF: 0.00173 AC: 2529 AN: 1461662 Hom.: 7 Cov.: 99 AF XY: 0.00171 AC XY: 1244 AN XY: 727136

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00197

Gnomad4 FIN exome AF: 0.000449

Gnomad4 NFE exome AF: 0.00203

Gnomad4 OTH exome AF: 0.000977

GnomAD4 genome AF: 0.00101 AC: 154 AN: 152246 Hom.: 1 Cov.: 31 AF XY: 0.000860 AC XY: 64 AN XY: 74446

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00194

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00160 Hom.: 0

Bravo AF: 0.000948

EpiCase AF: 0.00169

EpiControl AF: 0.00184

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 06, 2017	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 30, 2016

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.62
DANN	Benign	0.42

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: rs144796763; hg19: chr12-6128141;