rs2229444

chr12-6110516-G-Achr12-6110516-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000552.5(VWF):c.390C>T(p.Ser130=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00932 in 1,614,116 control chromosomes in the GnomAD database, including 917 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (84 hom., cov: 32)
  • Exomes 𝑓: 0.0088 (833 hom.)
• Consequence: VWF NM_000552.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.67

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 12-6110516-G-A is Benign according to our data. Variant chr12-6110516-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6110516-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.67 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWF	NM_000552.5	c.390C>T	p.Ser130=	synonymous_variant	5/52	ENST00000261405.10
VWF	XM_047429501.1	c.390C>T	p.Ser130=	synonymous_variant	5/52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWF	ENST00000261405.10	c.390C>T	p.Ser130=	synonymous_variant	5/52	1	NM_000552.5	P1
VWF	ENST00000321023.5	c.*449C>T		3_prime_UTR_variant, NMD_transcript_variant	6/7	1
VWF	ENST00000538635.5	n.419C>T		splice_region_variant, non_coding_transcript_exon_variant	5/6	4

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2173 AN: 152106 Hom.: 85 Cov.: 32

Gnomad AFR AF: 0.0222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00623

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.164

Gnomad SAS AF: 0.00746

Gnomad FIN AF: 0.00763

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00231

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.0174 AC: 4379 AN: 251490 Hom.: 269 AF XY: 0.0160 AC XY: 2173 AN XY: 135920

Gnomad AFR exome AF: 0.0215

Gnomad AMR exome AF: 0.00893

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.160

Gnomad SAS exome AF: 0.00738

Gnomad FIN exome AF: 0.00901

Gnomad NFE exome AF: 0.00262

Gnomad OTH exome AF: 0.00928

GnomAD4 exome AF: 0.00880 AC: 12864 AN: 1461892 Hom.: 833 Cov.: 31 AF XY: 0.00875 AC XY: 6363 AN XY: 727246

Gnomad4 AFR exome AF: 0.0201

Gnomad4 AMR exome AF: 0.00814

Gnomad4 ASJ exome AF: 0.000957

Gnomad4 EAS exome AF: 0.191

Gnomad4 SAS exome AF: 0.00791

Gnomad4 FIN exome AF: 0.00842

Gnomad4 NFE exome AF: 0.00222

Gnomad4 OTH exome AF: 0.00987

GnomAD4 genome AF: 0.0143 AC: 2177 AN: 152224 Hom.: 84 Cov.: 32 AF XY: 0.0147 AC XY: 1093 AN XY: 74424

Gnomad4 AFR AF: 0.0222

Gnomad4 AMR AF: 0.00622

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.165

Gnomad4 SAS AF: 0.00726

Gnomad4 FIN AF: 0.00763

Gnomad4 NFE AF: 0.00231

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00521 Hom.: 2

Bravo AF: 0.0152

Asia WGS AF: 0.0490 AC: 171 AN: 3478

EpiCase AF: 0.00256

EpiControl AF: 0.00237

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	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 03, 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	-0.43
Cadd	Benign	12
Dann	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2229444; hg19: chr12-6219682; COSMIC: COSV54614792;