12-6065248-T-G

Position:

• chr12-6065248-T-G

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.1182A>C​(p.Ser394Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,613,308 control chromosomes in the GnomAD database, including 26,030 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (6338 hom., cov: 33)
  • Exomes 𝑓: 0.15 (19692 hom.)
• Consequence: VWF NM_000552.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.113

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=-0.64).
• BP6: Variant 12-6065248-T-G is Benign according to our data. Variant chr12-6065248-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 256651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6065248-T-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.113 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5	c.1182A>C	p.Ser394Ser	synonymous_variant	11/52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.1182A>C	p.Ser394Ser	synonymous_variant	11/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.1182A>C	p.Ser394Ser	synonymous_variant	11/52	1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000538635.5	n.420+45267A>C		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.236 AC: 35874 AN: 151742 Hom.: 6314 Cov.: 33

Gnomad AFR AF: 0.500

Gnomad AMI AF: 0.0725

Gnomad AMR AF: 0.137

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: 0.195

GnomAD3 exomes AF: 0.165 AC: 41315 AN: 250660 Hom.: 4634 AF XY: 0.165 AC XY: 22315 AN XY: 135510

Gnomad AFR exome AF: 0.494

Gnomad AMR exome AF: 0.0861

Gnomad ASJ exome AF: 0.0916

Gnomad EAS exome AF: 0.228

Gnomad SAS exome AF: 0.240

Gnomad FIN exome AF: 0.107

Gnomad NFE exome AF: 0.130

Gnomad OTH exome AF: 0.145

GnomAD4 exome AF: 0.150 AC: 218684 AN: 1461448 Hom.: 19692 Cov.: 34 AF XY: 0.152 AC XY: 110187 AN XY: 727012

Gnomad4 AFR exome AF: 0.502

Gnomad4 AMR exome AF: 0.0927

Gnomad4 ASJ exome AF: 0.0904

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: 0.169

GnomAD4 genome AF: 0.237 AC: 35951 AN: 151860 Hom.: 6338 Cov.: 33 AF XY: 0.233 AC XY: 17288 AN XY: 74244

Gnomad4 AFR AF: 0.501

Gnomad4 AMR AF: 0.137

Gnomad4 ASJ AF: 0.0755

Gnomad4 EAS AF: 0.222

Gnomad4 SAS AF: 0.235

Gnomad4 FIN AF: 0.103

Gnomad4 NFE AF: 0.133

Gnomad4 OTH AF: 0.195

Alfa AF: 0.176 Hom.: 2504

Bravo AF: 0.250

Asia WGS AF: 0.245 AC: 850 AN: 3478

EpiCase AF: 0.130

EpiControl AF: 0.132

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

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 25, 2020	- -

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	-0.64
CADD	Benign	7.8
DANN	Benign	0.57

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: rs1800376; hg19: chr12-6174414; COSMIC: COSV54629344;