chr12-6019479-C-G

Position:

• chr12-6019479-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP5

The NM_000552.5(VWF):​c.3939G>C​(p.Trp1313Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 0.152

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a strand (size 16) in uniprot entity VWF_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_000552.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), VWF. . Gene score misZ 0.98969 (greater than the threshold 3.09). Trascript score misZ 3.5064 (greater than threshold 3.09). GenCC has associacion of gene with von Willebrand disease type 2M, hereditary von Willebrand disease, von Willebrand disease type 2B, von Willebrand disease type 2N, von Willebrand disease 2, von Willebrand disease type 2A, von Willebrand disease 3, von Willebrand disease 1.
• PP5: Variant 12-6019479-C-G is Pathogenic according to our data. Variant chr12-6019479-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 287.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-6019479-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5	c.3939G>C	p.Trp1313Cys	missense_variant	28/52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.3939G>C	p.Trp1313Cys	missense_variant	28/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.3939G>C	p.Trp1313Cys	missense_variant	28/52	1	NM_000552.5	ENSP00000261405	P1
VWF	ENST00000538635.5	n.421-25545G>C		intron_variant, non_coding_transcript_variant		4
VWF	ENST00000539641.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Von Willebrand disease type 2B Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2010

- -

not provided Other:1

not provided, no classification provided

literature only

Academic Unit of Haematology, University of Sheffield

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.31	N
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	A
PrimateAI	Benign	0.34	T
PROVEAN	Benign	2.6	N
REVEL	Uncertain	0.63
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.29
MutPred		0.77		Loss of MoRF binding (P = 0.0201);
MVP		0.85
MPC		0.70
ClinPred		0.49	T
GERP RS		-8.2
Varity_R		0.21
gMVP		0.80

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

Publications

LitVar

Other links and lift over

dbSNP: rs61749392; hg19: chr12-6128645;