rs7962217

chr12-5952393-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP6_Very_Strong BA1

The NM_000552.5(VWF):c.8113G>A(p.Gly2705Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0577 in 1,613,754 control chromosomes in the GnomAD database, including 3,226 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (204 hom., cov: 32)
  • Exomes 𝑓: 0.059 (3022 hom.)
• Consequence: VWF NM_000552.5 missense, splice_region
• Scores: Splicing: ADA: 0.9526
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 5.94

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 -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, VWF
• BP6: Variant 12-5952393-C-T is Benign according to our data. Variant chr12-5952393-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 256702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-5952393-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWF	NM_000552.5	c.8113G>A	p.Gly2705Arg	missense_variant, splice_region_variant	49/52	ENST00000261405.10
VWF	XM_047429501.1	c.8113G>A	p.Gly2705Arg	missense_variant, splice_region_variant	49/52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWF	ENST00000261405.10	c.8113G>A	p.Gly2705Arg	missense_variant, splice_region_variant	49/52	1	NM_000552.5	P1
VWF	ENST00000612016.1	n.522G>A		splice_region_variant, non_coding_transcript_exon_variant	2/3	5
VWF	ENST00000621700.1	n.431G>A		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes AF: 0.0448 AC: 6807 AN: 152098 Hom.: 204 Cov.: 32

Gnomad AFR AF: 0.0177

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.0433

Gnomad ASJ AF: 0.0360

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.0612

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0568

Gnomad OTH AF: 0.0449

GnomAD3 exomes AF: 0.0593 AC: 14897 AN: 251422 Hom.: 627 AF XY: 0.0641 AC XY: 8712 AN XY: 135880

Gnomad AFR exome AF: 0.0172

Gnomad AMR exome AF: 0.0702

Gnomad ASJ exome AF: 0.0337

Gnomad EAS exome AF: 0.00321

Gnomad SAS exome AF: 0.125

Gnomad FIN exome AF: 0.0595

Gnomad NFE exome AF: 0.0558

Gnomad OTH exome AF: 0.0518

GnomAD4 exome AF: 0.0591 AC: 86371 AN: 1461538 Hom.: 3022 Cov.: 32 AF XY: 0.0611 AC XY: 44423 AN XY: 727068

Gnomad4 AFR exome AF: 0.0162

Gnomad4 AMR exome AF: 0.0654

Gnomad4 ASJ exome AF: 0.0333

Gnomad4 EAS exome AF: 0.00202

Gnomad4 SAS exome AF: 0.125

Gnomad4 FIN exome AF: 0.0591

Gnomad4 NFE exome AF: 0.0577

Gnomad4 OTH exome AF: 0.0580

GnomAD4 genome AF: 0.0447 AC: 6798 AN: 152216 Hom.: 204 Cov.: 32 AF XY: 0.0448 AC XY: 3332 AN XY: 74432

Gnomad4 AFR AF: 0.0176

Gnomad4 AMR AF: 0.0432

Gnomad4 ASJ AF: 0.0360

Gnomad4 EAS AF: 0.00289

Gnomad4 SAS AF: 0.119

Gnomad4 FIN AF: 0.0612

Gnomad4 NFE AF: 0.0568

Gnomad4 OTH AF: 0.0445

Alfa AF: 0.0522 Hom.: 488

Bravo AF: 0.0414

TwinsUK AF: 0.0593 AC: 220

ALSPAC AF: 0.0602 AC: 232

ESP6500AA AF: 0.0197 AC: 87

ESP6500EA AF: 0.0578 AC: 497

ExAC AF: 0.0593 AC: 7197

Asia WGS AF: 0.0530 AC: 186 AN: 3478

EpiCase AF: 0.0601

EpiControl AF: 0.0566

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.32
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Pathogenic	3.1	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.29
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.30
MutPred		0.39		Gain of catalytic residue at L2702 (P = 0.0017);
MPC		1.0
ClinPred		0.024	T
GERP RS		5.5
Varity_R		0.53
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.95
dbscSNV1_RF	Pathogenic	0.79
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: rs7962217; hg19: chr12-6061559; COSMIC: COSV54621796;