12-6063036-T-C

Variant names:

• chr12-6063036-T-C
• rs1800378
• NM_000552.5:c.1451A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000552.5(VWF):​c.1451A>G​(p.His484Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.629 in 1,612,716 control chromosomes in the GnomAD database, including 327,980 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. H484L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.53 (24306 hom., cov: 32)
  • Exomes 𝑓: 0.64 (303674 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:9
• Conservation: PhyloP100: 0.268
• Publications: 55 publications found

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]

VWF Gene-Disease associations (from GenCC):

• hereditary von Willebrand disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• von Willebrand disease type 2B

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• von Willebrand disease 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• von Willebrand disease 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• von Willebrand disease type 2A

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• von Willebrand disease type 2M

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• von Willebrand disease 3

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• von Willebrand disease type 2N

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• PP2: Missense variant in the VWF gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 149 curated pathogenic missense variants (we use a threshold of 10). The gene has 28 curated benign missense variants. Gene score misZ: 0.98969 (below the threshold of 3.09). Trascript score misZ: 3.5064 (above the threshold of 3.09). GenCC associations: The gene is linked to hereditary von Willebrand disease, von Willebrand disease type 2B, von Willebrand disease 1, von Willebrand disease 2, von Willebrand disease type 2A, von Willebrand disease type 2M, von Willebrand disease 3, von Willebrand disease type 2N.
• BP4: Computational evidence support a benign effect (MetaRNN=7.129097E-6).
• BP6: Variant 12-6063036-T-C is Benign according to our data. Variant chr12-6063036-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.687 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000552.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	NM_000552.5	MANE Select	c.1451A>G	p.His484Arg	missense	Exon 13 of 52	NP_000543.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWF	ENST00000261405.10	TSL:1 MANE Select	c.1451A>G	p.His484Arg	missense	Exon 13 of 52	ENSP00000261405.5
	VWF	ENST00000538635.5	TSL:4	n.420+47479A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.526 AC: 80019 AN: 151984 Hom.: 24308 Cov.: 32

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.656

Gnomad AMR AF: 0.542

Gnomad ASJ AF: 0.722

Gnomad EAS AF: 0.692

Gnomad SAS AF: 0.707

Gnomad FIN AF: 0.674

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.657

Gnomad OTH AF: 0.566

GnomAD2 exomes AF: 0.621 AC: 155009 AN: 249536 AF XY: 0.638

Gnomad AFR exome AF: 0.198

Gnomad AMR exome AF: 0.524

Gnomad ASJ exome AF: 0.733

Gnomad EAS exome AF: 0.704

Gnomad FIN exome AF: 0.671

Gnomad NFE exome AF: 0.654

Gnomad OTH exome AF: 0.650

GnomAD4 exome AF: 0.640 AC: 934494 AN: 1460614 Hom.: 303674 Cov.: 55 AF XY: 0.644 AC XY: 468245 AN XY: 726682

African (AFR) AF: 0.200 AC: 6710 AN: 33476

American (AMR) AF: 0.526 AC: 23494 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.729 AC: 19038 AN: 26128

East Asian (EAS) AF: 0.670 AC: 26603 AN: 39688

South Asian (SAS) AF: 0.705 AC: 60799 AN: 86212

European-Finnish (FIN) AF: 0.667 AC: 35179 AN: 52716

Middle Eastern (MID) AF: 0.699 AC: 4032 AN: 5768

European-Non Finnish (NFE) AF: 0.648 AC: 720760 AN: 1111582

Other (OTH) AF: 0.628 AC: 37879 AN: 60364

GnomAD4 genome AF: 0.526 AC: 80033 AN: 152102 Hom.: 24306 Cov.: 32 AF XY: 0.532 AC XY: 39557 AN XY: 74358

African (AFR) AF: 0.206 AC: 8529 AN: 41486

American (AMR) AF: 0.541 AC: 8275 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.722 AC: 2504 AN: 3470

East Asian (EAS) AF: 0.692 AC: 3570 AN: 5162

South Asian (SAS) AF: 0.707 AC: 3415 AN: 4830

European-Finnish (FIN) AF: 0.674 AC: 7128 AN: 10574

Middle Eastern (MID) AF: 0.673 AC: 198 AN: 294

European-Non Finnish (NFE) AF: 0.657 AC: 44630 AN: 67964

Other (OTH) AF: 0.562 AC: 1187 AN: 2112

Alfa AF: 0.623 Hom.: 139413

Bravo AF: 0.502

TwinsUK AF: 0.650 AC: 2411

ALSPAC AF: 0.664 AC: 2559

ESP6500AA AF: 0.219 AC: 966

ESP6500EA AF: 0.657 AC: 5649

ExAC AF: 0.618 AC: 75019

Asia WGS AF: 0.615 AC: 2138 AN: 3478

EpiCase AF: 0.665

EpiControl AF: 0.662

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Allele frequency is common in at least one population database (frequency: 73.314% in gnomAD_ExomesFounderPop) based on the frequency threshold of 0.5% for this gene. Variant was observed in a homozygous state in population databases more than expected for disease.

not specified Benign:3

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

von Willebrand disease type 2 Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

von Willebrand disease type 3 Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

von Willebrand disease type 1 Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary von Willebrand disease Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	6.8
DANN	Benign	0.54
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0000071	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.41	N
PhyloP100		0.27
PrimateAI	Benign	0.34	T
PROVEAN	Benign	1.7	N
REVEL	Benign	0.063
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.017	B
Vest4		0.062
MPC		0.30
ClinPred		0.0019	T
GERP RS		1.3
Varity_R		0.057
gMVP		0.47
Mutation Taster		=90/10	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1800378; hg19: chr12-6172202; COSMIC: COSV54614099;