rs1800385

chr12-6018725-C-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000552.5(VWF):c.4693G>T(p.Val1565Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,613,044 control chromosomes in the GnomAD database, including 14,229 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.094 (1304 hom., cov: 31)
  • Exomes 𝑓: 0.11 (12925 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.997

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 -17 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000552.5
• PP2: Missense variant where missense usually causes diseases, VWF
• BP4: Computational evidence support a benign effect (MetaRNN=0.004629165).
• BP6: Variant 12-6018725-C-A is Benign according to our data. Variant chr12-6018725-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 256682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6018725-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.358 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWF	NM_000552.5	c.4693G>T	p.Val1565Leu	missense_variant	28/52	ENST00000261405.10
VWF	XM_047429501.1	c.4693G>T	p.Val1565Leu	missense_variant	28/52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWF	ENST00000261405.10	c.4693G>T	p.Val1565Leu	missense_variant	28/52	1	NM_000552.5	P1
VWF	ENST00000538635.5	n.421-24791G>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0943 AC: 14342 AN: 152016 Hom.: 1294 Cov.: 31

Gnomad AFR AF: 0.0232

Gnomad AMI AF: 0.0231

Gnomad AMR AF: 0.245

Gnomad ASJ AF: 0.0746

Gnomad EAS AF: 0.371

Gnomad SAS AF: 0.219

Gnomad FIN AF: 0.0374

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0849

Gnomad OTH AF: 0.101

GnomAD3 exomes AF: 0.154 AC: 38488 AN: 250486 Hom.: 5181 AF XY: 0.148 AC XY: 20081 AN XY: 135430

Gnomad AFR exome AF: 0.0204

Gnomad AMR exome AF: 0.371

Gnomad ASJ exome AF: 0.0788

Gnomad EAS exome AF: 0.385

Gnomad SAS exome AF: 0.205

Gnomad FIN exome AF: 0.0427

Gnomad NFE exome AF: 0.0846

Gnomad OTH exome AF: 0.119

GnomAD4 exome AF: 0.107 AC: 156186 AN: 1460910 Hom.: 12925 Cov.: 56 AF XY: 0.109 AC XY: 79001 AN XY: 726682

Gnomad4 AFR exome AF: 0.0177

Gnomad4 AMR exome AF: 0.354

Gnomad4 ASJ exome AF: 0.0769

Gnomad4 EAS exome AF: 0.396

Gnomad4 SAS exome AF: 0.200

Gnomad4 FIN exome AF: 0.0450

Gnomad4 NFE exome AF: 0.0855

Gnomad4 OTH exome AF: 0.112

GnomAD4 genome AF: 0.0944 AC: 14368 AN: 152134 Hom.: 1304 Cov.: 31 AF XY: 0.100 AC XY: 7464 AN XY: 74382

Gnomad4 AFR AF: 0.0232

Gnomad4 AMR AF: 0.246

Gnomad4 ASJ AF: 0.0746

Gnomad4 EAS AF: 0.372

Gnomad4 SAS AF: 0.218

Gnomad4 FIN AF: 0.0374

Gnomad4 NFE AF: 0.0849

Gnomad4 OTH AF: 0.105

Alfa AF: 0.0936 Hom.: 397

Bravo AF: 0.108

TwinsUK AF: 0.0787 AC: 292

ALSPAC AF: 0.0843 AC: 325

ESP6500AA AF: 0.0234 AC: 103

ESP6500EA AF: 0.0803 AC: 691

ExAC AF: 0.144 AC: 17431

Asia WGS AF: 0.287 AC: 995 AN: 3478

EpiCase AF: 0.0791

EpiControl AF: 0.0836

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 17, 2023	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 12, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

von Willebrand disease type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

von Willebrand disease type 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

von Willebrand disease type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Hereditary von Willebrand disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	14
Dann	Benign	0.93
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.18
Sift	Benign	0.38	T
Sift4G	Benign	0.68	T
Polyphen		0.0	B
Vest4		0.088
MutPred		0.74		Gain of catalytic residue at V1565 (P = 0.0014);
MPC		0.27
ClinPred		0.0010	T
GERP RS		1.9
Varity_R		0.22
gMVP		0.76

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: rs1800385; hg19: chr12-6127891; COSMIC: COSV54618442; COSMIC: COSV54618442;