chr12-6018581-A-G

Variant names:

• chr12-6018581-A-G
• rs61750581
• NM_000552.5:c.4837T>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PP4_Moderate PP3 PM2_Supporting PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The c.4837T>C variant in VWF is a missense variant predicted to cause substitution of Serine by Proline at amino acid 1613 (p.Ser1613Pro). At least 1 patient (Patient 14 from PMID:38053262) with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of very low VWF activity as indicated by a VWF activity-to-antigen ratio <0.7, and loss of high molecular weight multimers, which together are highly specific for VWD type 2A. Additional consistent phenotypes were also reported in the patient including a FVIII activity consistent with VWF antigen (ratio >0.7) (PP4_Moderate). This variant has been reported in one additional proband (Zimmerman program) with activity/antigen ratio <0.37, abnormal multimers, and normal platelet binding (PS4_Supporting). The computational predictor REVEL gives a score of 0.7, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). This variant is absent from gnomAD v4.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as VUS for autosomal recessive von Willebrand disease type 2A based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS4_Supporting, PP4_Moderate, PP3 and PM2_Supporting (VCEP specifications version 1.0.0; date of approval). LINK:https://erepo.genome.network/evrepo/ui/classification/CA114131/MONDO:0015628/081

• Frequency: Genomes: not found (cov: 31)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 O:1
• Conservation: PhyloP100: 3.61
• 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: Uncertain_significance. The variant received 5 ACMG points.

• 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.4837T>C	p.Ser1613Pro	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.4837T>C	p.Ser1613Pro	missense	Exon 28 of 52	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.4837T>C	p.Ser1613Pro	missense	Exon 29 of 53	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2967+10761T>C		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	1	-	Von Willebrand disease type 2A (2)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		3.6
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.8	N
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.46
MutPred		0.82		Gain of catalytic residue at G1609 (P = 0.0101)
MVP		0.89
MPC		0.90
ClinPred		0.92	D
GERP RS		2.3
Varity_R		0.89
gMVP		0.95
Mutation Taster		=15/85	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: rs61750581; hg19: chr12-6127747;