10-73997944-A-G

Variant names:

• chr10-73997944-A-G
• rs3812625
• ENST00000623461.3:n.79+723A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The ENST00000623461.3(VCL):​n.79+723A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.34 in 152,044 control chromosomes in the GnomAD database, including 9,969 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.34 (9969 hom., cov: 33)
• Consequence: VCL ENST00000623461.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.03
• Publications: 6 publications found

Genes affected

VCL (HGNC:12665): (vinculin) Vinculin is a cytoskeletal protein associated with cell-cell and cell-matrix junctions, where it is thought to function as one of several interacting proteins involved in anchoring F-actin to the membrane. Defects in VCL are the cause of cardiomyopathy dilated type 1W. Dilated cardiomyopathy is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Multiple alternatively spliced transcript variants have been found for this gene, but the biological validity of some variants has not been determined. [provided by RefSeq, Jul 2008]

VCL Gene-Disease associations (from GenCC):

• dilated cardiomyopathy 1W

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypertrophic cardiomyopathy 15

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 10-73997944-A-G is Benign according to our data. Variant chr10-73997944-A-G is described in ClinVar as [Benign]. Clinvar id is 684060.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.525 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCL	NM_014000.3	c.-264A>G		upstream_gene_variant		ENST00000211998.10	NP_054706.1
VCL	NM_003373.4	c.-264A>G		upstream_gene_variant			NP_003364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCL	ENST00000211998.10	c.-264A>G		upstream_gene_variant		1	NM_014000.3	ENSP00000211998.5

Frequencies

GnomAD3 genomes AF: 0.340 AC: 51605 AN: 151926 Hom.: 9931 Cov.: 33

Gnomad AFR AF: 0.530

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.313

Gnomad ASJ AF: 0.309

Gnomad EAS AF: 0.273

Gnomad SAS AF: 0.280

Gnomad FIN AF: 0.289

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.251

Gnomad OTH AF: 0.319

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.340 AC: 51699 AN: 152044 Hom.: 9969 Cov.: 33 AF XY: 0.341 AC XY: 25342 AN XY: 74306

African (AFR) AF: 0.531 AC: 22031 AN: 41504

American (AMR) AF: 0.314 AC: 4792 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.309 AC: 1073 AN: 3472

East Asian (EAS) AF: 0.273 AC: 1400 AN: 5124

South Asian (SAS) AF: 0.279 AC: 1346 AN: 4820

European-Finnish (FIN) AF: 0.289 AC: 3060 AN: 10588

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.251 AC: 17085 AN: 67938

Other (OTH) AF: 0.320 AC: 676 AN: 2110

Alfa AF: 0.203 Hom.: 672

Bravo AF: 0.346

Asia WGS AF: 0.305 AC: 1062 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Benign	0.74
PhyloP100		1.0
PromoterAI		-0.024	Neutral

Splicing

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

Other links and lift over

dbSNP: rs3812625; hg19: chr10-75757702;