12-6018667-T-C

Variant names:

• chr12-6018667-T-C
• rs1800386
• NM_000552.5:c.4751A>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PS3 PP2 PP5 BP4

The NM_000552.5(VWF):​c.4751A>G​(p.Tyr1584Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00344 in 1,613,678 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,risk factor (no stars). ClinVar reports functional evidence for this variant: "SCV000602319: Functional studies have shown that this variant causes decreased VWF protein levels, decreased VWF protein function, (PMID:16985174 (2007), 23355534 (2013), 23426949 (2013), 25103891 (2014)), and increased susceptibility of the VWF protein to proteolysis (PMID:14525793 (2004), 19506354 (2009), 21346256 (2011))." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0036 (15 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity; risk factor criteria provided, conflicting classifications P:22 U:8 O:4
• Conservation: PhyloP100: 3.59
• Publications: 61 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.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000602319: Functional studies have shown that this variant causes decreased VWF protein levels, decreased VWF protein function, (PMID: 16985174 (2007), 23355534 (2013), 23426949 (2013), 25103891 (2014)), and increased susceptibility of the VWF protein to proteolysis (PMID: 14525793 (2004), 19506354 (2009), 21346256 (2011)).; SCV001159609: Functional studies indicate that this variant protein results in decreased protein synthesis and increased cellular retention in vitro, with increased susceptibility of VWF proteolysis in vivo (Bowen 2005, O’Brien 2003, Pruss 2011). PMID: 14525793. PMID: 15755288. PMID: 21346256.; SCV001653003: In vitro functional studies provide some evidence that this variant impacts protein function (O'Brien 2003 PMID: 12649144, Pruss 2011 PMID: 21346256); however, these types of assays may not accurately represent biological function. Animal models in mice have shown that this variant causes decreased thrombus formation (Pruss 2011 PMID: 21346256).; SCV001431531: Functional assays have shown that this variant results in a decrease of protein production and expression when compared to wildtype.; SCV005398857: "This variant has moderate functional evidence supporting abnormal protein function (PMID: 21346256; 12649144)."; SCV002555870: Experimental studies have demonstrated that the Y1584C variant results in decreased biosynthesis and secretion in vitro (e.g. O'Brien_2003), together with an increased susceptibility to proteolysis by ADAMTS13 (e.g. Pruss_2011). PMID:22197721, PMID:28971901; SCV005417787: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."
• 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.
• PP5: Variant 12-6018667-T-C is Pathogenic according to our data. Variant chr12-6018667-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity|risk_factor. ClinVar VariationId is 310.
• BP4: Computational evidence support a benign effect (MetaRNN=0.044336706). . Strength limited to SUPPORTING due to the PP5.

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.4751A>G	p.Tyr1584Cys	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.4751A>G	p.Tyr1584Cys	missense	Exon 28 of 52	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.4751A>G	p.Tyr1584Cys	missense	Exon 29 of 53	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2967+10675A>G		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes AF: 0.00226 AC: 343 AN: 151988 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000411

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00387

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00266 AC: 667 AN: 251146 AF XY: 0.00269

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00338

Gnomad NFE exome AF: 0.00412

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00357 AC: 5212 AN: 1461572 Hom.: 15 Cov.: 41 AF XY: 0.00349 AC XY: 2534 AN XY: 727026

African (AFR) AF: 0.000538 AC: 18 AN: 33476

American (AMR) AF: 0.00152 AC: 68 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00310 AC: 81 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.000499 AC: 43 AN: 86256

European-Finnish (FIN) AF: 0.00437 AC: 233 AN: 53360

Middle Eastern (MID) AF: 0.00209 AC: 12 AN: 5748

European-Non Finnish (NFE) AF: 0.00412 AC: 4580 AN: 1111814

Other (OTH) AF: 0.00293 AC: 177 AN: 60376

GnomAD4 genome AF: 0.00226 AC: 343 AN: 152106 Hom.: 0 Cov.: 31 AF XY: 0.00207 AC XY: 154 AN XY: 74346

African (AFR) AF: 0.000410 AC: 17 AN: 41500

American (AMR) AF: 0.00144 AC: 22 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4806

European-Finnish (FIN) AF: 0.00226 AC: 24 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00387 AC: 263 AN: 67968

Other (OTH) AF: 0.00332 AC: 7 AN: 2108

Alfa AF: 0.00312 Hom.: 4

Bravo AF: 0.00197

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00302 AC: 26

ExAC AF: 0.00293 AC: 356

EpiCase AF: 0.00447

EpiControl AF: 0.00456

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity; risk factor

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
8	5	-	not provided (14)
5	-	-	von Willebrand disease type 1 (6)
3	-	-	Hereditary von Willebrand disease (4)
2	1	-	von Willebrand disease type 2 (3)
-	1	-	Inborn genetic diseases (1)
-	1	-	Thrombocytopenia (1)
1	-	-	Thrombus (1)
1	-	-	von Willebrand disease type 1;C1264040:von Willebrand disease type 2;C1264041:von Willebrand disease type 3 (1)
1	-	-	von Willebrand disorder (1)
1	-	-	VWF-related disorder (1)
-	-	-	VON WILLEBRAND DISEASE, TYPE 1, SUSCEPTIBILITY TO (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Benign	0.044	T
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		3.6
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.39	N
REVEL	Uncertain	0.64
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.013	D
Polyphen		0.99	D
Vest4		0.82
MVP		0.81
MPC		0.39
ClinPred		0.085	T
GERP RS		5.0
Varity_R		0.79
gMVP		0.89
Mutation Taster		=57/43	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: rs1800386; hg19: chr12-6127833; COSMIC: COSV108094747; COSMIC: COSV108094747;