rs1800379

chr12-6058030-A-Gchr12-6058030-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000552.5(VWF):c.1548T>C(p.Tyr516=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.364 in 1,612,916 control chromosomes in the GnomAD database, including 111,546 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (14101 hom., cov: 32)
  • Exomes 𝑓: 0.36 (97445 hom.)
• Consequence: VWF NM_000552.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:9
• Conservation: PhyloP100: 0.193

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 12-6058030-A-G is Benign according to our data. Variant chr12-6058030-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 256655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6058030-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.193 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.592 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWF	NM_000552.5	c.1548T>C	p.Tyr516=	synonymous_variant	14/52	ENST00000261405.10
VWF	XM_047429501.1	c.1548T>C	p.Tyr516=	synonymous_variant	14/52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWF	ENST00000261405.10	c.1548T>C	p.Tyr516=	synonymous_variant	14/52	1	NM_000552.5	P1
VWF	ENST00000538635.5	n.420+52485T>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.410 AC: 62259 AN: 152026 Hom.: 14071 Cov.: 32

Gnomad AFR AF: 0.597

Gnomad AMI AF: 0.418

Gnomad AMR AF: 0.275

Gnomad ASJ AF: 0.331

Gnomad EAS AF: 0.186

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.356

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.363

Gnomad OTH AF: 0.396

GnomAD3 exomes AF: 0.334 AC: 82849 AN: 248268 Hom.: 15354 AF XY: 0.335 AC XY: 45232 AN XY: 134984

Gnomad AFR exome AF: 0.608

Gnomad AMR exome AF: 0.173

Gnomad ASJ exome AF: 0.341

Gnomad EAS exome AF: 0.178

Gnomad SAS exome AF: 0.316

Gnomad FIN exome AF: 0.366

Gnomad NFE exome AF: 0.368

Gnomad OTH exome AF: 0.343

GnomAD4 exome AF: 0.359 AC: 524289 AN: 1460772 Hom.: 97445 Cov.: 51 AF XY: 0.357 AC XY: 259598 AN XY: 726712

Gnomad4 AFR exome AF: 0.613

Gnomad4 AMR exome AF: 0.185

Gnomad4 ASJ exome AF: 0.337

Gnomad4 EAS exome AF: 0.176

Gnomad4 SAS exome AF: 0.310

Gnomad4 FIN exome AF: 0.368

Gnomad4 NFE exome AF: 0.369

Gnomad4 OTH exome AF: 0.365

GnomAD4 genome AF: 0.410 AC: 62330 AN: 152144 Hom.: 14101 Cov.: 32 AF XY: 0.402 AC XY: 29918 AN XY: 74382

Gnomad4 AFR AF: 0.598

Gnomad4 AMR AF: 0.274

Gnomad4 ASJ AF: 0.331

Gnomad4 EAS AF: 0.185

Gnomad4 SAS AF: 0.300

Gnomad4 FIN AF: 0.356

Gnomad4 NFE AF: 0.363

Gnomad4 OTH AF: 0.392

Alfa AF: 0.363 Hom.: 16914

Bravo AF: 0.410

Asia WGS AF: 0.293 AC: 1023 AN: 3478

EpiCase AF: 0.355

EpiControl AF: 0.363

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 29, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 25, 2021	- -
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: 60.792% 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. A synonymous variant not located in a splice region. -

not specified Benign:3

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	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.74
Dann	Benign	0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1800379; hg19: chr12-6167196; COSMIC: COSV54614779;