rs33978901

chr12-6031493-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 3P and 12B. PM5 PP2 BP4_Strong BS1 BS2

The NM_000552.5(VWF):c.2771G>A(p.Arg924Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0177 in 1,614,096 control chromosomes in the GnomAD database, including 297 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R924W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (13 hom., cov: 31)
  • Exomes 𝑓: 0.018 (284 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:8 O:1
• Conservation: PhyloP100: 0.511

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 Benign. Variant got -9 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-6031494-G-A is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant where missense usually causes diseases, VWF
• BP4: Computational evidence support a benign effect (MetaRNN=0.00859642).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0118 (1799/152226) while in subpopulation NFE AF= 0.0202 (1374/68008). AF 95% confidence interval is 0.0193. There are 13 homozygotes in gnomad4. There are 816 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1799 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWF	NM_000552.5	c.2771G>A	p.Arg924Gln	missense_variant	21/52	ENST00000261405.10
VWF	XM_047429501.1	c.2771G>A	p.Arg924Gln	missense_variant	21/52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWF	ENST00000261405.10	c.2771G>A	p.Arg924Gln	missense_variant	21/52	1	NM_000552.5	P1
VWF	ENST00000538635.5	n.421-37559G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1799 AN: 152108 Hom.: 13 Cov.: 31

Gnomad AFR AF: 0.00370

Gnomad AMI AF: 0.0176

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.00509

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0202

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.0105 AC: 2647 AN: 251494 Hom.: 30 AF XY: 0.0107 AC XY: 1449 AN XY: 135922

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.00448

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00366

Gnomad FIN exome AF: 0.00550

Gnomad NFE exome AF: 0.0186

Gnomad OTH exome AF: 0.0112

GnomAD4 exome AF: 0.0184 AC: 26843 AN: 1461870 Hom.: 284 Cov.: 31 AF XY: 0.0178 AC XY: 12950 AN XY: 727236

Gnomad4 AFR exome AF: 0.00293

Gnomad4 AMR exome AF: 0.00425

Gnomad4 ASJ exome AF: 0.00329

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00351

Gnomad4 FIN exome AF: 0.00620

Gnomad4 NFE exome AF: 0.0224

Gnomad4 OTH exome AF: 0.0153

GnomAD4 genome AF: 0.0118 AC: 1799 AN: 152226 Hom.: 13 Cov.: 31 AF XY: 0.0110 AC XY: 816 AN XY: 74448

Gnomad4 AFR AF: 0.00368

Gnomad4 AMR AF: 0.0101

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.00509

Gnomad4 NFE AF: 0.0202

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.0172 Hom.: 41

Bravo AF: 0.0112

TwinsUK AF: 0.0194 AC: 72

ALSPAC AF: 0.0226 AC: 87

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0212 AC: 182

ExAC AF: 0.0106 AC: 1290

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0192

EpiControl AF: 0.0159

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:8 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3 Other:1

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	VWF: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 29, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 03, 2023	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
not provided, no classification provided	literature only	Academic Unit of Haematology, University of Sheffield	-	- -

von Willebrand disease type 2 Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	research	Laboratory of Hematology, Radboud University Medical Center	May 06, 2022	- -
Benign, no assertion criteria provided	clinical testing	Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico	Apr 26, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

von Willebrand disease type 1 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	research	Laboratory of Hematology, Radboud University Medical Center	May 06, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

von Willebrand disease type 3 Benign:2

Likely benign, 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 -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

Hereditary von Willebrand disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Dec 13, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	19
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.0086	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	0.85	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.089
Sift	Benign	0.16	T
Sift4G	Benign	0.15	T
Polyphen		0.023	B
Vest4		0.13
MPC		0.24
ClinPred		0.0062	T
GERP RS		3.8
Varity_R		0.088
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs33978901; hg19: chr12-6140659; COSMIC: COSV99075173;