chr12-5952393-C-T

Variant names:

• chr12-5952393-C-T
• rs7962217
• NM_000552.5:c.8113G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The NM_000552.4(VWF):c.8113G>A (p.Gly2705Arg) variant in VWF is a missense variant predicted to cause substitution of Glycine by Arginine at amino acid 2705. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.1227 (based on 11352/91062 alleles in the South Asian population, including 829 homozygotes), which is higher than the ClinGen VWD VCEP threshold of >0.1 for BA1. As reported in PMID:26105150 the variant is significantly associated with lower plasma levels of FVIII but not vWF. In summary this variant is classified as Benign for VWD based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BA1 LINK:https://erepo.genome.network/evrepo/ui/classification/CA6401404/MONDO:0019565/090

• 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 reviewed by expert panel B:9
• Conservation: PhyloP100: 5.94
• Publications: 27 publications found

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 Gene-Disease associations (from GenCC):

• hereditary von Willebrand disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• von Willebrand disease 2

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• von Willebrand disease type 2B

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• von Willebrand disease 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• von Willebrand disease type 2A

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• von Willebrand disease type 2M

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• von Willebrand disease 3

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• von Willebrand disease type 2N

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000552.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	NM_000552.5	MANE Select	c.8113G>A	p.Gly2705Arg	missense splice_region	Exon 49 of 52	NP_000543.3	P04275-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	ENST00000261405.10	TSL:1 MANE Select	c.8113G>A	p.Gly2705Arg	missense splice_region	Exon 49 of 52	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.8113G>A	p.Gly2705Arg	missense splice_region	Exon 50 of 53	ENSP00000565738.1
	VWF	ENST00000895680.1		c.3193G>A	p.Gly1065Arg	missense splice_region	Exon 24 of 27	ENSP00000565739.1

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

GnomAD2 exomes AF: 0.0593 AC: 14897 AN: 251422 AF XY: 0.0641

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 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

African (AFR) AF: 0.0162 AC: 543 AN: 33472

American (AMR) AF: 0.0654 AC: 2923 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0333 AC: 869 AN: 26132

East Asian (EAS) AF: 0.00202 AC: 80 AN: 39688

South Asian (SAS) AF: 0.125 AC: 10779 AN: 86244

European-Finnish (FIN) AF: 0.0591 AC: 3156 AN: 53382

Middle Eastern (MID) AF: 0.0584 AC: 337 AN: 5768

European-Non Finnish (NFE) AF: 0.0577 AC: 64182 AN: 1111760

Other (OTH) AF: 0.0580 AC: 3502 AN: 60380

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

African (AFR) AF: 0.0176 AC: 730 AN: 41532

American (AMR) AF: 0.0432 AC: 661 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0360 AC: 125 AN: 3470

East Asian (EAS) AF: 0.00289 AC: 15 AN: 5184

South Asian (SAS) AF: 0.119 AC: 573 AN: 4818

European-Finnish (FIN) AF: 0.0612 AC: 649 AN: 10608

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0568 AC: 3860 AN: 67990

Other (OTH) AF: 0.0445 AC: 94 AN: 2114

Alfa AF: 0.0517 Hom.: 968

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

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Hereditary von Willebrand disease (2)
-	-	1	not provided (1)
-	-	1	von Willebrand disease type 1 (1)
-	-	1	von Willebrand disease type 2 (1)
-	-	1	von Willebrand disease type 3 (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		5.9
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
Mutation Taster		=29/71	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7962217; hg19: chr12-6061559; COSMIC: COSV54621796;