rs143054357

Positions:

• chr12-6095571-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP6 BS2_Supporting

The ENST00000261405.10(VWF):​c.546G>A​(p.Ser182=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00145 in 1,614,110 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0015 (6 hom.)
• Consequence: VWF ENST00000261405.10 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: -4.13

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 Likely_benign. Variant got -2 ACMG points.

• BP6: Variant 12-6095571-C-T is Benign according to our data. Variant chr12-6095571-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 256684.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=4}.
• BS2: High AC in GnomAd4 at 186 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWF	NM_000552.5	c.546G>A	p.Ser182=	synonymous_variant	6/52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.546G>A	p.Ser182=	synonymous_variant	6/52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.546G>A	p.Ser182=	synonymous_variant	6/52	1	NM_000552.5	ENSP00000261405	P1
VWF	ENST00000321023.5	c.*605G>A		3_prime_UTR_variant, NMD_transcript_variant	7/7	1		ENSP00000461331
VWF	ENST00000538635.5	n.420+14944G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 186 AN: 152130 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00179

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00124 AC: 312 AN: 251476 Hom.: 0 AF XY: 0.00127 AC XY: 173 AN XY: 135912

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00246

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000849

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00161

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00148 AC: 2159 AN: 1461862 Hom.: 6 Cov.: 31 AF XY: 0.00145 AC XY: 1053 AN XY: 727232

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.00203

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00102

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.00168

Gnomad4 OTH exome AF: 0.00156

GnomAD4 genome AF: 0.00122 AC: 186 AN: 152248 Hom.: 0 Cov.: 31 AF XY: 0.00121 AC XY: 90 AN XY: 74438

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.00275

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00179

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00146 Hom.: 0

Bravo AF: 0.00128

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00180

EpiControl AF: 0.00184

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 22, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2023	Observed with a variant on the opposite allele (in trans) in a patient with type 1 von Willebrand disease (VWD) in the published literature (Borrs et al., 2019), and observed with a variant in cis and a variant in trans in a patient with type 3 VWD in the published literature (Corrales et al., 2009; Borrs et al., 2019); Published functional studies demonstrate a damaging effect by affect splicing of VWF mRNA (Borrs et al., 2019); This variant is associated with the following publications: (PMID: 19277422, 36307006, 34708896, 30361419) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2019	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 27, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

von Willebrand disease type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn

Nov 26, 2021

- -

von Willebrand disease type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.025
DANN	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.41		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.41		Position offset: 13

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs143054357; hg19: chr12-6204737;