rs546732699

Positions:

• chr12-6022792-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_000552.5(VWF):​c.3486A>G​(p.Pro1162=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (525 hom., cov: 10)
  • Exomes 𝑓: 0.0082 (276 hom.)
  • Failed GnomAD Quality Control
• Consequence: VWF NM_000552.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.66

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 12-6022792-T-C is Benign according to our data. Variant chr12-6022792-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 256670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6022792-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.66 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5	c.3486A>G	p.Pro1162=	synonymous_variant	26/52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.3486A>G	p.Pro1162=	synonymous_variant	26/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.3486A>G	p.Pro1162=	synonymous_variant	26/52	1	NM_000552.5	ENSP00000261405	P1
VWF	ENST00000538635.5	n.421-28858A>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0542 AC: 4843 AN: 89306 Hom.: 523 Cov.: 10

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.0178

Gnomad AMR AF: 0.0302

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000540

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0185

Gnomad NFE AF: 0.000962

Gnomad OTH AF: 0.0650

GnomAD3 exomes AF: 0.0256 AC: 1391 AN: 54270 Hom.: 125 AF XY: 0.0228 AC XY: 624 AN XY: 27356

Gnomad AFR exome AF: 0.221

Gnomad AMR exome AF: 0.0179

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00122

Gnomad OTH exome AF: 0.00990

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00825 AC: 3624 AN: 439440 Hom.: 276 Cov.: 0 AF XY: 0.00702 AC XY: 1628 AN XY: 231798

Gnomad4 AFR exome AF: 0.209

Gnomad4 AMR exome AF: 0.0184

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000489

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000897

Gnomad4 OTH exome AF: 0.0165

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0543 AC: 4855 AN: 89346 Hom.: 525 Cov.: 10 AF XY: 0.0545 AC XY: 2159 AN XY: 39602

Gnomad4 AFR AF: 0.208

Gnomad4 AMR AF: 0.0300

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000541

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000962

Gnomad4 OTH AF: 0.0644

Alfa AF: 0.0865 Hom.: 77

Bravo AF: 0.0730

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

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	GeneDx	Nov 12, 2018	- -

not specified Benign:1

Likely 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	-0.94
CADD	Benign	0.11
DANN	Benign	0.41

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: rs546732699; hg19: chr12-6131958; COSMIC: COSV54619636; COSMIC: COSV54619636;