rs200586078

chr12-6056985-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The NM_000552.5(VWF):c.1817G>A(p.Arg606Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000224 in 1,545,114 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 0.460

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 -7 ACMG points.

• PP2: Missense variant where missense usually causes diseases, VWF
• BP4: Computational evidence support a benign effect (MetaRNN=0.008060724).
• BS2: High AC in GnomAd at 184 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWF	NM_000552.5	c.1817G>A	p.Arg606Gln	missense_variant	15/52	ENST00000261405.10
VWF	XM_047429501.1	c.1817G>A	p.Arg606Gln	missense_variant	15/52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWF	ENST00000261405.10	c.1817G>A	p.Arg606Gln	missense_variant	15/52	1	NM_000552.5	P1
VWF	ENST00000538635.5	n.420+53530G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00121 AC: 184 AN: 152204 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00417

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000208 AC: 30 AN: 144058 Hom.: 0 AF XY: 0.000153 AC XY: 12 AN XY: 78350

Gnomad AFR exome AF: 0.00337

Gnomad AMR exome AF: 0.0000398

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000871

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000233

GnomAD4 exome AF: 0.000116 AC: 162 AN: 1392792 Hom.: 1 Cov.: 31 AF XY: 0.000106 AC XY: 73 AN XY: 687914

Gnomad4 AFR exome AF: 0.00388

Gnomad4 AMR exome AF: 0.000110

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000550

Gnomad4 SAS exome AF: 0.0000503

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000277

Gnomad4 OTH exome AF: 0.000413

GnomAD4 genome AF: 0.00121 AC: 184 AN: 152322 Hom.: 0 Cov.: 31 AF XY: 0.00113 AC XY: 84 AN XY: 74478

Gnomad4 AFR AF: 0.00416

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000154 Hom.: 0

Bravo AF: 0.00148

ESP6500AA AF: 0.00243 AC: 10

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000199 AC: 22

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 19, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 22, 2023	Variant summary: VWF c.1817G>A (p.Arg606Gln) results in a conservative amino acid change located in the VWF/SSPO/Zonadhesin-like, cysteine-rich domain (IPR014853) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 144058 control chromosomes, predominantly at a frequency of 0.0034 within the African or African-American subpopulation in the gnomAD database. To our knowledge, no occurrence of c.1817G>A in individuals affected with Von Willebrand Disease and no experimental evidence demonstrating its impact on protein function have been reported. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 16, 2023	The variant has not been reported in individuals with vWF-related conditions in the published literature. The frequency of this variant in the general population, 0.0046 (77/16714 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. Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on VWF mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites . Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

von Willebrand disease type 1;C1264040:von Willebrand disease type 2;C1264041:von Willebrand disease type 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 22, 2021

- -

VWF-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 22, 2023

The VWF c.1817G>A variant is predicted to result in the amino acid substitution p.Arg606Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.46% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-6166151-C-T). 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	0.066
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	15
Dann	Benign	0.97
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.85	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.0081	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.17	N
MutationTaster	Benign	0.98	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.17
Sift	Benign	0.92	T
Sift4G	Benign	0.34	T
Polyphen		0.037	B
Vest4		0.11
MVP		0.41
MPC		0.22
ClinPred		0.034	T
GERP RS		-3.7
Varity_R		0.032
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs200586078; hg19: chr12-6166151;