12-6021961-G-T

Variant names:

• chr12-6021961-G-T
• rs373787920
• NM_000552.5:c.3613C>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_000552.5(VWF):​c.3613C>A​(p.Arg1205Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,886 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 Likely pathogenic (★). ClinVar reports functional evidence for this variant: "SCV005202105: Published functional studies demonstrate deficiency of VWF through enhanced macrophage-mediated clearance (Rawley et al., 2015)". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1205C) has been classified as Likely pathogenic. The gene VWF is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.98
• Publications: 0 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: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005202105: Published functional studies demonstrate deficiency of VWF through enhanced macrophage-mediated clearance (Rawley et al., 2015)
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-6021961-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 439332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.894
• PP5: Variant 12-6021961-G-T is Pathogenic according to our data. Variant chr12-6021961-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3338883.Status of the report is criteria_provided_single_submitter, 1 stars.

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.3613C>A	p.Arg1205Ser	missense	Exon 27 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.3613C>A	p.Arg1205Ser	missense	Exon 27 of 52	ENSP00000261405.5	P04275-1
	VWF	ENST00000895679.1		c.3613C>A	p.Arg1205Ser	missense	Exon 28 of 53	ENSP00000565738.1
	VWF	ENST00000895680.1		c.2967+7381C>A		intron	N/A	ENSP00000565739.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727242

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: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.058	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		4.0
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.26
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.83	P
Vest4		0.87
MutPred		0.62		Gain of catalytic residue at R1205 (P = 0)
MVP		0.76
MPC		0.78
ClinPred		0.95	D
GERP RS		4.7
Varity_R		0.29
gMVP		0.80
Mutation Taster		=7/93	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: rs373787920; hg19: chr12-6131127;