rs141087261

Variant names:

• chr12-6029409-C-T
• rs141087261
• NM_000552.5:c.2900G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-6029409-C-T
• chr12-6029409-C-A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. BS1 PP4

This summary comes from the ClinGen Evidence Repository: NM_000552.5:c.2900G>A is a missense variant in VWF that replaces glycine with aspartic acid at position 967. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.02526 (based on 967/75012 alleles in the African / African-American population, with 34 homozygotes), which is higher than the ClinGen VWD VCEP threshold of >0.01 (BS1). This variant has been reported in at least 1 patient with a diagnosis of VWD Type 3 and a phenotype including reduced quantity of VWF antigen. However, PP4 was not met due to the absence of other phenotype details and the presence of two additional variants (p.C350AfsX107 and p.C2774W) without reported confirmation of phase (PMID:23777763). This variant has also been reported in the heterozygous state in at least 7 reported healthy control individuals with no bleeding history and normal lab values (PMID:22197721). However, BS2 has not been considered since this code is not applicable to the gene-disease relationship due to incomplete penetrance. In summary, this variant meets the criteria to be classified as a variant of unknown significance for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: BS1, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6402913/MONDO:0019565/090

• Frequency:
  • Genomes: 𝑓 0.0077 (18 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (17 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Likely benign reviewed by expert panel U:3 B:9
• Conservation: PhyloP100: 5.69
• Publications: 5 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: Likely_benign. The variant received -3 ACMG points.

• PP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: 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.2900G>A	p.Gly967Asp	missense	Exon 22 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.2900G>A	p.Gly967Asp	missense	Exon 22 of 52	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.2900G>A	p.Gly967Asp	missense	Exon 23 of 53	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2900G>A	p.Gly967Asp	missense	Exon 22 of 27	ENSP00000565739.1

Frequencies

GnomAD3 genomes AF: 0.00766 AC: 1166 AN: 152132 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0264

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00192 AC: 483 AN: 251372 AF XY: 0.00139

Gnomad AFR exome AF: 0.0257

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000749 AC: 1095 AN: 1461882 Hom.: 17 Cov.: 31 AF XY: 0.000622 AC XY: 452 AN XY: 727244

African (AFR) AF: 0.0260 AC: 872 AN: 33480

American (AMR) AF: 0.00192 AC: 86 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1112012

Other (OTH) AF: 0.00190 AC: 115 AN: 60396

GnomAD4 genome AF: 0.00767 AC: 1167 AN: 152250 Hom.: 18 Cov.: 32 AF XY: 0.00752 AC XY: 560 AN XY: 74440

African (AFR) AF: 0.0264 AC: 1095 AN: 41532

American (AMR) AF: 0.00359 AC: 55 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68028

Other (OTH) AF: 0.00427 AC: 9 AN: 2110

Alfa AF: 0.00278 Hom.: 10

Bravo AF: 0.00903

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0247 AC: 109

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00242 AC: 294

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	3	4	not provided (7)
-	-	1	Hereditary von Willebrand disease (1)
-	-	1	not specified (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	Benign	0.11
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.86	D
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.58	N
PhyloP100		5.7
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.96	D
Vest4		0.64
MVP		0.82
MPC		0.86
ClinPred		0.035	T
GERP RS		3.7
Varity_R		0.33
gMVP		0.88
Mutation Taster		=6/94	disease causing

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

Other links and lift over

dbSNP: rs141087261; hg19: chr12-6138575; COSMIC: COSV99075178;