rs61754011

Variant names:

• chr12-6057930-C-G
• rs61754011
• NM_000552.5:c.1648G>C

Your query was ambiguous. Multiple possible variants found:

• chr12-6057930-C-G
• chr12-6057930-C-T
• chr12-6057930-C-A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS1 PM2 PP2 PP3_Moderate

The NM_000552.5(VWF):​c.1648G>C​(p.Gly550Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. The gene VWF is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.64
• Publications: 9 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

Specifications for VWF are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PS1: Transcript NM_000552.5 (VWF) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the VWF gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 149 curated pathogenic missense variants (we use a threshold of 10). The gene has 28 curated benign missense variants. Gene score misZ: 0.98969 (below the threshold of 3.09). Trascript score misZ: 3.5064 (above the threshold of 3.09). GenCC associations: The gene is linked to von Willebrand disease type 2N, von Willebrand disease type 2B, von Willebrand disease type 2M, von Willebrand disease 2, hereditary von Willebrand disease, von Willebrand disease type 2A, von Willebrand disease 1, von Willebrand disease 3.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.902

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.1648G>C	p.Gly550Arg	missense	Exon 14 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.1648G>C	p.Gly550Arg	missense	Exon 14 of 52	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.1648G>C	p.Gly550Arg	missense	Exon 15 of 53	ENSP00000565738.1
	VWF	ENST00000895680.1		c.1648G>C	p.Gly550Arg	missense	Exon 14 of 27	ENSP00000565739.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461384 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727008

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44720

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53008

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111954

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.056	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		5.6
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.55		Gain of catalytic residue at A552 (P = 0.0058)
MVP		0.86
MPC		0.82
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.56
gMVP		0.98
Mutation Taster		=17/83	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: rs61754011; hg19: chr12-6167096;