rs1063856

chr12-6044368-T-Cchr12-6044368-T-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 5P and 20B. PM1 PM5 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000552.5(VWF):c.2365A>G(p.Thr789Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.356 in 1,613,858 control chromosomes in the GnomAD database, including 107,997 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. T789P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.40 (13217 hom., cov: 33)
  • Exomes 𝑓: 0.35 (94780 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:10
• Conservation: PhyloP100: 0.942

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 -15 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000552.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-6044368-T-G is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant where missense usually causes diseases, VWF
• BP4: Computational evidence support a benign effect (MetaRNN=6.430792E-5).
• BP6: Variant 12-6044368-T-C is Benign according to our data. Variant chr12-6044368-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 256659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6044368-T-C is described in Lovd as [Benign]. Variant chr12-6044368-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.57 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWF	NM_000552.5	c.2365A>G	p.Thr789Ala	missense_variant	18/52	ENST00000261405.10
VWF	XM_047429501.1	c.2365A>G	p.Thr789Ala	missense_variant	18/52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWF	ENST00000261405.10	c.2365A>G	p.Thr789Ala	missense_variant	18/52	1	NM_000552.5	P1
VWF	ENST00000538635.5	n.421-50434A>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.395 AC: 60042 AN: 151930 Hom.: 13190 Cov.: 33

Gnomad AFR AF: 0.576

Gnomad AMI AF: 0.386

Gnomad AMR AF: 0.270

Gnomad ASJ AF: 0.295

Gnomad EAS AF: 0.0782

Gnomad SAS AF: 0.235

Gnomad FIN AF: 0.354

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.372

GnomAD3 exomes AF: 0.312 AC: 78459 AN: 251226 Hom.: 14078 AF XY: 0.311 AC XY: 42243 AN XY: 135794

Gnomad AFR exome AF: 0.582

Gnomad AMR exome AF: 0.176

Gnomad ASJ exome AF: 0.297

Gnomad EAS exome AF: 0.0702

Gnomad SAS exome AF: 0.249

Gnomad FIN exome AF: 0.361

Gnomad NFE exome AF: 0.363

Gnomad OTH exome AF: 0.324

GnomAD4 exome AF: 0.352 AC: 514079 AN: 1461810 Hom.: 94780 Cov.: 59 AF XY: 0.348 AC XY: 253379 AN XY: 727206

Gnomad4 AFR exome AF: 0.583

Gnomad4 AMR exome AF: 0.190

Gnomad4 ASJ exome AF: 0.294

Gnomad4 EAS exome AF: 0.0709

Gnomad4 SAS exome AF: 0.249

Gnomad4 FIN exome AF: 0.358

Gnomad4 NFE exome AF: 0.371

Gnomad4 OTH exome AF: 0.351

GnomAD4 genome AF: 0.395 AC: 60108 AN: 152048 Hom.: 13217 Cov.: 33 AF XY: 0.387 AC XY: 28788 AN XY: 74336

Gnomad4 AFR AF: 0.576

Gnomad4 AMR AF: 0.269

Gnomad4 ASJ AF: 0.295

Gnomad4 EAS AF: 0.0774

Gnomad4 SAS AF: 0.236

Gnomad4 FIN AF: 0.354

Gnomad4 NFE AF: 0.362

Gnomad4 OTH AF: 0.368

Alfa AF: 0.357 Hom.: 25219

Bravo AF: 0.400

TwinsUK AF: 0.370 AC: 1372

ALSPAC AF: 0.377 AC: 1453

ESP6500AA AF: 0.568 AC: 2504

ESP6500EA AF: 0.357 AC: 3074

ExAC AF: 0.323 AC: 39189

Asia WGS AF: 0.204 AC: 710 AN: 3478

EpiCase AF: 0.354

EpiControl AF: 0.362

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:3

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	Allele frequency is common in at least one population database (frequency: 58.215% in gnomAD_Exomes) 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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 02, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 08, 2018	This variant is associated with the following publications: (PMID: 32521332, 30817071, 30046743, 18923835, 23636243, 21163921, 23690449, 21534939) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2016	- -

not specified Benign:3

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

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	0.049
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	16
Dann	Benign	0.77
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.046	T
MetaRNN	Benign	0.000064	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.0	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.94	N
REVEL	Benign	0.18
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.048
MPC		0.18
ClinPred		0.00037	T
GERP RS		2.2
Varity_R		0.17
gMVP		0.55

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: rs1063856; hg19: chr12-6153534; COSMIC: COSV54612011;