12-6019004-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000552.5(VWF):c.4414G>C(p.Asp1472His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,613,312 control chromosomes in the GnomAD database, including 17,108 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1472P?) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.21 (5738 hom., cov: 31)
  • Exomes 𝑓: 0.10 (11370 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.121

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, VWF
• BP4: Computational evidence support a benign effect (MetaRNN=2.40032E-5).
• BP6: Variant 12-6019004-C-G is Benign according to our data. Variant chr12-6019004-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 256679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6019004-C-G is described in Lovd as [Likely_benign]. Variant chr12-6019004-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.494 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWF	NM_000552.5	c.4414G>C	p.Asp1472His	missense_variant	28/52	ENST00000261405.10
VWF	XM_047429501.1	c.4414G>C	p.Asp1472His	missense_variant	28/52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWF	ENST00000261405.10	c.4414G>C	p.Asp1472His	missense_variant	28/52	1	NM_000552.5	P1
VWF	ENST00000538635.5	n.421-25070G>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.208 AC: 31589 AN: 151844 Hom.: 5730 Cov.: 31

Gnomad AFR AF: 0.500

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.0576

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.148

Gnomad FIN AF: 0.0760

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.0903

Gnomad OTH AF: 0.207

GnomAD3 exomes AF: 0.119 AC: 29448 AN: 248378 Hom.: 3144 AF XY: 0.116 AC XY: 15611 AN XY: 134782

Gnomad AFR exome AF: 0.509

Gnomad AMR exome AF: 0.0733

Gnomad ASJ exome AF: 0.0597

Gnomad EAS exome AF: 0.110

Gnomad SAS exome AF: 0.144

Gnomad FIN exome AF: 0.0768

Gnomad NFE exome AF: 0.0886

Gnomad OTH exome AF: 0.105

GnomAD4 exome AF: 0.104 AC: 152489 AN: 1461350 Hom.: 11370 Cov.: 99 AF XY: 0.104 AC XY: 75805 AN XY: 726966

Gnomad4 AFR exome AF: 0.518

Gnomad4 AMR exome AF: 0.0798

Gnomad4 ASJ exome AF: 0.0582

Gnomad4 EAS exome AF: 0.108

Gnomad4 SAS exome AF: 0.146

Gnomad4 FIN exome AF: 0.0761

Gnomad4 NFE exome AF: 0.0909

Gnomad4 OTH exome AF: 0.123

GnomAD4 genome AF: 0.208 AC: 31629 AN: 151962 Hom.: 5738 Cov.: 31 AF XY: 0.205 AC XY: 15247 AN XY: 74276

Gnomad4 AFR AF: 0.500

Gnomad4 AMR AF: 0.127

Gnomad4 ASJ AF: 0.0576

Gnomad4 EAS AF: 0.115

Gnomad4 SAS AF: 0.148

Gnomad4 FIN AF: 0.0760

Gnomad4 NFE AF: 0.0903

Gnomad4 OTH AF: 0.205

Alfa AF: 0.0764 Hom.: 238

Bravo AF: 0.226

TwinsUK AF: 0.0882 AC: 327

ALSPAC AF: 0.0877 AC: 338

ESP6500AA AF: 0.393 AC: 1717

ESP6500EA AF: 0.0657 AC: 565

ExAC AF: 0.129 AC: 15584

EpiCase AF: 0.0910

EpiControl AF: 0.0912

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 20, 2023	- -

von Willebrand disease type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

von Willebrand disease type 2M Benign:1

Benign, criteria provided, single submitter

clinical testing

Versiti Diagnostic Laboratories, Versiti, Inc

Aug 04, 2017

The missense variant c.4414G>C in exon 28 of the VWF gene changes aspartic acid at codon 1472 to histidine (p.D1472H). The p.D1472H variant is common in the general population (12%, Exome Aggregation Consortium) and frequently found in individuals of African descent (50%, Exome Aggregation Consortium). Although the p.D1472H variant is not thought to cause type 1 or 2M von Willebrand disease (Flood, 2010), individuals who are heterozygous or homozygous for p.D1472H may exhibit reduced ratio of VWF ristocetin cofactor activity to VWF antigen. However, p.D1472H does not have physiological consequences; specifically it does not affect VWF multimer distribution or ristocetin-independent binding of VWF to GP1b complex, and does not result in increased risk for bleeding. In summary, VWF c.4414G>C, p.D1472H, is a benign variant with respect to von Willebrand disease. -

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	0.065
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	0.083
Dann	Benign	0.22
DEOGEN2	Benign	0.27	T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0048	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.000024	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.18	N
REVEL	Benign	0.19
Sift	Benign	0.15	T
Sift4G	Benign	0.17	T
Polyphen		0.0	B
Vest4		0.040
MPC		0.32
ClinPred		0.0065	T
GERP RS		0.81
Varity_R		0.032
gMVP		0.49

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: rs1800383; hg19: chr12-6128170; COSMIC: COSV54620580; COSMIC: COSV54620580;