NM_000552.5:c.4022G>A

Variant names:

• chr12-6019396-C-T
• rs61749403
• NM_000552.5:c.4022G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS3 PS4 PP4_Moderate PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000552.5(VWF):c.4022G>A (p.Arg1341Gln) variant in VWF has been reported in several dozen vWD type 2B patients. At least one (P8 of PMID:20118404) has sufficient information reported to meet the PP4_moderate criteria, including mucocutaneous bleeding, positive GOF assay, and loss of HMW multimers. An additional four have been curated for inclusion based on at least a LD-RIPA response (PMIDs: 20118404, 8292729; PS4_strong). In vitro studies have shown increased platelet binding in COS-7 cells and a VWF -/- mouse with R1306-vWF hydrodynamic expression recapitulated patient phenotypes (PS3). The Grpmax filtering allele frequency in gnomAD v4.1 is 2.800e-7 (based on 2/1179864 alleles in the European non-Finnish population), which is lower than the ClinGen VWD VCEP threshold of <0.0001 (PM2_Supporting). This variant is predicted deleterious by REVEL gives a score of 0.792, which is above the ClinGen VWD VCEP threshold of >0.644 (PP3). This variant has been observed segregating in multiple families, however insufficient phenotypic information has been reported on those individuals. In summary, this variant meets criteria to be classified as pathogenic for vWD type 2B with specified criteria PS3, PS4, PM2_supporting, PP3, and PP4_moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA114129/MONDO:0015629/081

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6 U:1 O:2
• Conservation: PhyloP100: 1.87
• Publications: 18 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: Pathogenic. The variant received 12 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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.4022G>A	p.Arg1341Gln	missense	Exon 28 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.4022G>A	p.Arg1341Gln	missense	Exon 28 of 52	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.4022G>A	p.Arg1341Gln	missense	Exon 29 of 53	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2967+9946G>A		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250664 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461630 Hom.: 0 Cov.: 38 AF XY: 0.00000138 AC XY: 1 AN XY: 727126

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111842

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (3)
1	1	-	von Willebrand disease type 2 (2)
2	-	-	Von Willebrand disease type 2B (2)
1	-	-	VWF-related disorder (1)
-	-	-	Hereditary von Willebrand disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		1.9
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.5	N
REVEL	Pathogenic	0.79
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.78		Gain of helix (P = 0.0325)
MVP		0.85
MPC		0.92
ClinPred		0.89	D
GERP RS		5.0
Varity_R		0.58
gMVP		0.71
Mutation Taster		=22/78	disease causing (ClinVar)

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: rs61749403; hg19: chr12-6128562;