chr12-5949134-A-G

Position:

• chr12-5949134-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The ENST00000261405.10(VWF):​c.8323T>C​(p.Ser2775Pro) 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 Uncertain significance (no stars). Synonymous variant affecting the same amino acid position (i.e. S2775S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: VWF ENST00000261405.10 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 1.01

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a domain CTCK (size 88) in uniprot entity VWF_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in ENST00000261405.10
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5	c.8323T>C	p.Ser2775Pro	missense_variant	52/52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.8323T>C	p.Ser2775Pro	missense_variant	52/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.8323T>C	p.Ser2775Pro	missense_variant	52/52	1	NM_000552.5	ENSP00000261405	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

von Willebrand disease type 3 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico

Nov 01, 2020

ClinGen Pathogenicity Calculator -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.019
Eigen_PC	Benign	-0.062
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.071	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Pathogenic	2.9	M
MutationTaster	Benign	0.69	D
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.27
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.61	P
Vest4		0.48
MutPred		0.47		Gain of catalytic residue at S2775 (P = 0);
MVP		0.71
MPC		0.35
ClinPred		0.45	T
GERP RS		2.4
Varity_R		0.61
gMVP		0.96

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-6058300;