12-6021995-A-G

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.3579T>C(p.Pro1193=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,614,118 control chromosomes in the GnomAD database, including 1,896 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (1011 hom., cov: 31)
  • Exomes 𝑓: 0.0068 (885 hom.)
• Consequence: VWF NM_000552.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.99

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=-0.93).
• BP6: Variant 12-6021995-A-G is Benign according to our data. Variant chr12-6021995-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 256673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6021995-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.99 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWF	NM_000552.5	c.3579T>C	p.Pro1193=	synonymous_variant	27/52	ENST00000261405.10
VWF	XM_047429501.1	c.3579T>C	p.Pro1193=	synonymous_variant	27/52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWF	ENST00000261405.10	c.3579T>C	p.Pro1193=	synonymous_variant	27/52	1	NM_000552.5	P1
VWF	ENST00000538635.5	n.421-28061T>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0639 AC: 9719 AN: 152112 Hom.: 1008 Cov.: 31

Gnomad AFR AF: 0.218

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0312

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00123

Gnomad OTH AF: 0.0617

GnomAD3 exomes AF: 0.0171 AC: 4307 AN: 251494 Hom.: 406 AF XY: 0.0127 AC XY: 1725 AN XY: 135920

Gnomad AFR exome AF: 0.224

Gnomad AMR exome AF: 0.0137

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00114

Gnomad OTH exome AF: 0.00896

GnomAD4 exome AF: 0.00682 AC: 9970 AN: 1461888 Hom.: 885 Cov.: 31 AF XY: 0.00593 AC XY: 4315 AN XY: 727248

Gnomad4 AFR exome AF: 0.223

Gnomad4 AMR exome AF: 0.0150

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000689

Gnomad4 OTH exome AF: 0.0152

GnomAD4 genome AF: 0.0640 AC: 9744 AN: 152230 Hom.: 1011 Cov.: 31 AF XY: 0.0616 AC XY: 4582 AN XY: 74436

Gnomad4 AFR AF: 0.218

Gnomad4 AMR AF: 0.0311

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00123

Gnomad4 OTH AF: 0.0611

Alfa AF: 0.0160 Hom.: 100

Bravo AF: 0.0739

Asia WGS AF: 0.0180 AC: 62 AN: 3478

EpiCase AF: 0.00174

EpiControl AF: 0.00142

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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 22, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 28, 2022	- -

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
BayesDel_noAF	Benign	-0.93
Cadd	Benign	0.19
Dann	Benign	0.32

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: rs16933969; hg19: chr12-6131161;