12-5994115-A-T

Position:

• chr12-5994115-A-T

Variant summary

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

The ENST00000261405.10(VWF):​c.6345T>A​(p.Thr2115=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00783 in 1,614,176 control chromosomes in the GnomAD database, including 850 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (471 hom., cov: 31)
  • Exomes 𝑓: 0.0042 (379 hom.)
• Consequence: VWF ENST00000261405.10 synonymous
• Clinical Significance: Benign reviewed by expert panel B:7
• Conservation: PhyloP100: -5.34

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=-0.95).
• BP6: Variant 12-5994115-A-T is Benign according to our data. Variant chr12-5994115-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 256690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-5994115-A-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-5.34 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5	c.6345T>A	p.Thr2115=	synonymous_variant	37/52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.6345T>A	p.Thr2115=	synonymous_variant	37/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.6345T>A	p.Thr2115=	synonymous_variant	37/52	1	NM_000552.5	ENSP00000261405	P1
VWF	ENST00000538635.5	n.421-181T>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0425 AC: 6461 AN: 152174 Hom.: 472 Cov.: 31

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0177

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.0377

GnomAD3 exomes AF: 0.0112 AC: 2807 AN: 251256 Hom.: 206 AF XY: 0.00827 AC XY: 1123 AN XY: 135812

Gnomad AFR exome AF: 0.151

Gnomad AMR exome AF: 0.00781

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000414

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00421 AC: 6156 AN: 1461884 Hom.: 379 Cov.: 32 AF XY: 0.00362 AC XY: 2632 AN XY: 727242

Gnomad4 AFR exome AF: 0.145

Gnomad4 AMR exome AF: 0.00892

Gnomad4 ASJ exome AF: 0.00103

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000278

Gnomad4 OTH exome AF: 0.00871

GnomAD4 genome AF: 0.0425 AC: 6475 AN: 152292 Hom.: 471 Cov.: 31 AF XY: 0.0402 AC XY: 2991 AN XY: 74484

Gnomad4 AFR AF: 0.147

Gnomad4 AMR AF: 0.0176

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.0373

Alfa AF: 0.0135 Hom.: 42

Bravo AF: 0.0483

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 11, 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	-0.95
CADD	Benign	0.013
DANN	Benign	0.46

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: rs11537642; hg19: chr12-6103281;