rs61748478

Variant names:

• chr12-6044349-T-C
• rs61748478
• NM_000552.5:c.2384A>G

Your query was ambiguous. Multiple possible variants found:

• chr12-6044349-T-C
• chr12-6044349-T-G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP4_Moderate PP3 PM2_Supporting PS3 PM3

This summary comes from the ClinGen Evidence Repository: The NM_000552.5(VWF):c.2384A>G (p.Tyr795Cys) missense variant has a Grpmax filtering allele frequency in gnomAD v4.1 of 2.800e-7 (based on 2/1180036 alleles in the European non-Finnish population), which is lower than the ClinGen VWD VCEP threshold of <0.005 for type 2N (PM2_Supporting). The computational predictor REVEL gives a score of 0.688, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). At least three compound heterozygous VWD type 2N patients have been reported with this variant; two (PMIDs: 33807613, 15461624; PM3) compound heterozygous with R854Q (classified Pathogenic by the VWD VCEP), and one (PMID:15213842) compound heterozygous with R1566X (not yet been evaluated by the VWD VCEP). At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as low FVIII activity (0.13 IU/ml) and decreased VWF:FVIII binding (<1.5%), which is highly specific for VWD type 2N. (PP4_moderate, PMID:15213842). Factor VIII binding assay performed with theY795C recombinant mutant showed severely impaired binding indicating that this variant has a damaging effect on protein function (PMID:15213842, 15461624; PS3). In summary, this variant meets the criteria to be classified as Pathogenic for von Willebrand disease type 2N. ACMG/AMP criteria applied as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PM2_supporting, PP3, PM3, PP4_moderate, PS3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA114166/MONDO:0015631/090

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:2 O:1
• Conservation: PhyloP100: 2.72
• Publications: 7 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 type 2B

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

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• von Willebrand disease 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• 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 10 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5	c.2384A>G	p.Tyr795Cys	missense_variant	Exon 18 of 52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.2384A>G	p.Tyr795Cys	missense_variant	Exon 18 of 52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.2384A>G	p.Tyr795Cys	missense_variant	Exon 18 of 52	1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000538635.5	n.421-50415A>G		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461882 Hom.: 0 Cov.: 61 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

von Willebrand disease type 2N Pathogenic:2

Oct 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 07, 2025

ClinGen von Willebrand Disease Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000552.5(VWF):c.2384A>G (p.Tyr795Cys) missense variant has a Grpmax filtering allele frequency in gnomAD v4.1 of 2.800e-7 (based on 2/1180036 alleles in the European non-Finnish population), which is lower than the ClinGen VWD VCEP threshold of <0.005 for type 2N (PM2_Supporting). The computational predictor REVEL gives a score of 0.688, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). At least three compound heterozygous VWD type 2N patients have been reported with this variant; two (PMIDs: 33807613, 15461624; PM3) compound heterozygous with R854Q (classified Pathogenic by the VWD VCEP), and one (PMID: 15213842) compound heterozygous with R1566X (not yet been evaluated by the VWD VCEP). At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as low FVIII activity (0.13 IU/ml) and decreased VWF:FVIII binding (<1.5%), which is highly specific for VWD type 2N. (PP4_moderate, PMID:15213842). Factor VIII binding assay performed with theY795C recombinant mutant showed severely impaired binding indicating that this variant has a damaging effect on protein function (PMID: 15213842, 15461624; PS3). In summary, this variant meets the criteria to be classified as Pathogenic for von Willebrand disease type 2N. ACMG/AMP criteria applied as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PM2_supporting, PP3, PM3, PP4_moderate, PS3. -

not provided Other:1

-

Academic Unit of Haematology, University of Sheffield

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.7
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.62		Gain of catalytic residue at L797 (P = 0.0022);
MVP		0.90
MPC		0.84
ClinPred		0.92	D
GERP RS		4.2
Varity_R		0.76
gMVP		0.86
Mutation Taster		=46/54	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: rs61748478; hg19: chr12-6153515;