NM_000552.5:c.6859C>T

Variant names:

• chr12-5985605-G-A
• rs61750625
• NM_000552.5:c.6859C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PS3_Supporting

This summary comes from the ClinGen Evidence Repository: NM_000552.5:c.6859C>T is a missense variant in VWF that replaces arginine with tryptophan at position 2287. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.008368 (based on 670/75044 alleles in African / African-American population, with 3 homozygotes). This intermediate allele frequency is lower than the ClinGen VWD VCEP threshold for BS1 (>0.01) but higher than the threshold for PM2_Supporting (<0.0001). At least 2 patients harboring this variant displayed a laboratory phenotype that led to a diagnosis of either VWD Type 2A (PMID:23340442) or VWD Type 2M (PMID:16321553), with the former patient exhibiting loss of high-molecular weight VWF multimers and VWF:CB/VWF:Ag ratio <0.7. However, this phenotype was not sufficiently detailed to meet the PP4 code. This variant has been observed once in the homozygous state in gnomAD, and two other healthy controls harboring the variant have been reported with normal lab values (PMID:22197721). However, BS2 has not been evaluated because this code is not considered applicable to VWD due to incomplete penetrance. A number of published control individuals have been found to harbor this variant, but were associated with a 35-40 IU/dL per allele decrease in VWF:Ag level and a smaller (non-significant) decrease in FVIII:C level (PMID:23690449). Exogenous expression of the variant in COS-1 cells showed normal multimerization but subnormal levels of protein secreted into the medium (50-70% of wild-type, though evidence of abnormal retention in the cell was absent). This quantitative but not qualitative defect does not meet the requirements for use by the ClinGen VWD VCEP for functional evaluation of VWD Type 2 variants, but may be a match for VWD Type 1. 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: PS3_Supporting. While published data do not make a conclusive case that this variant is disease-causing by itself, they indicate that this variant has functional impact and raise the possibility that it may act as a risk factor. LINK:https://erepo.genome.network/evrepo/ui/classification/CA228760/MONDO:0019565/090

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00028 (3 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:10 O:1
• Conservation: PhyloP100: 1.36
• Publications: 13 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: Uncertain_significance. The variant received 1 ACMG points.

• PS3: 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.6859C>T	p.Arg2287Trp	missense	Exon 39 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.6859C>T	p.Arg2287Trp	missense	Exon 39 of 52	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.6859C>T	p.Arg2287Trp	missense	Exon 40 of 53	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2968-32011C>T		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes AF: 0.00237 AC: 361 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000586 AC: 147 AN: 251052 AF XY: 0.000398

Gnomad AFR exome AF: 0.00806

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000278 AC: 406 AN: 1461790 Hom.: 3 Cov.: 33 AF XY: 0.000228 AC XY: 166 AN XY: 727190

African (AFR) AF: 0.00980 AC: 328 AN: 33480

American (AMR) AF: 0.000313 AC: 14 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53328

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1112006

Other (OTH) AF: 0.000513 AC: 31 AN: 60394

GnomAD4 genome AF: 0.00238 AC: 363 AN: 152332 Hom.: 0 Cov.: 33 AF XY: 0.00238 AC XY: 177 AN XY: 74488

African (AFR) AF: 0.00823 AC: 342 AN: 41564

American (AMR) AF: 0.00124 AC: 19 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00205 Hom.: 0

Bravo AF: 0.00259

ESP6500AA AF: 0.00613 AC: 27

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000659 AC: 80

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	6	-	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 1;C1264040:von Willebrand disease type 2;C1264041:von Willebrand disease type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.077
FATHMM_MKL	Benign	0.47	N
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		1.4
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.83
MVP		0.76
MPC		0.94
ClinPred		0.083	T
GERP RS		1.6
Varity_R		0.15
gMVP		0.72
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs61750625; hg19: chr12-6094771; COSMIC: COSV54616449;