rs143743709

chr12-5949079-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. PM1 PP2 BP4_Strong BS2

The NM_000552.5(VWF):c.8378T>C(p.Val2793Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00029 in 1,614,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 2.93

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_benign. 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 NM_000552.5
• PP2: Missense variant where missense usually causes diseases, VWF
• BP4: Computational evidence support a benign effect (MetaRNN=0.0059850514).
• BS2: High AC in GnomAd at 237 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWF	NM_000552.5	c.8378T>C	p.Val2793Ala	missense_variant	52/52	ENST00000261405.10
VWF	XM_047429501.1	c.8378T>C	p.Val2793Ala	missense_variant	52/52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWF	ENST00000261405.10	c.8378T>C	p.Val2793Ala	missense_variant	52/52	1	NM_000552.5	P1

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 237 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00528

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000466 AC: 117 AN: 250990 Hom.: 0 AF XY: 0.000354 AC XY: 48 AN XY: 135690

Gnomad AFR exome AF: 0.00580

Gnomad AMR exome AF: 0.000666

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000157 AC: 230 AN: 1461858 Hom.: 0 Cov.: 31 AF XY: 0.000140 AC XY: 102 AN XY: 727220

Gnomad4 AFR exome AF: 0.00541

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.00156 AC: 238 AN: 152354 Hom.: 0 Cov.: 33 AF XY: 0.00141 AC XY: 105 AN XY: 74508

Gnomad4 AFR AF: 0.00529

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000210 Hom.: 0

Bravo AF: 0.00195

ESP6500AA AF: 0.00613 AC: 27

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000445 AC: 54

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 31, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 02, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in healthy controls in the published literature (Bellissimo et al., 2012; Sadler et al., 2021); This variant is associated with the following publications: (PMID: 26420797, 33556167, 22197721) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 06, 2022	In the published literature, this variant has been reported in healthy individuals (PMID: 22197721 (2012), 33556167 (2022)). The frequency of this variant in the general population, 0.0058 (145/24922 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 22, 2024	Variant summary: VWF c.8378T>C (p.Val2793Ala) results in a non-conservative amino acid change located in the Cystine knot, C-terminal domain (IPR006207) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00047 in 250990 control chromosomes. c.8378T>C has been reported in the literature in healthy control individuals and Haemolytic uraemic syndrome patients (example, Bellissimo_2012, Sadler_2021, Connaughton_2023) but to our knowledge it has not been reported in individuals affected with Von Willebrand Disease. These report(s) do not provide unequivocal conclusions about association of the variant with Von Willebrand Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22197721, 37466676, 33556167). ClinVar contains an entry for this variant (Variation ID: 437264). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 19, 2017	- -

VWF-related condition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 18, 2023

The VWF c.8378T>C variant is predicted to result in the amino acid substitution p.Val2793Ala. This variant has been reported in healthy controls (Bellissimo et al. 2011. PubMed ID: 22197721; Sadler et al. 2021. PubMed ID: 33556167. Table S2). This variant is reported in 0.58% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-6058245-A-G). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	17
Dann	Benign	0.80
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.10
Sift	Benign	0.12	T
Sift4G	Benign	0.11	T
Polyphen		0.083	B
Vest4		0.19
MVP		0.36
MPC		0.66
ClinPred		0.043	T
GERP RS		5.0
Varity_R		0.27
gMVP		0.70

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: rs143743709; hg19: chr12-6058245;