rs1908339

Positions:

• chr10-74083342-T-A
• chr10-74083342-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014000.3(VCL):​c.875-24T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.586 in 1,611,454 control chromosomes in the GnomAD database, including 287,558 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.66 (35053 hom., cov: 32)
  • Exomes 𝑓: 0.58 (252505 hom.)
• Consequence: VCL NM_014000.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.867

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: This place is a probable branch point but likely benign (scored 3 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 10-74083342-T-A is Benign according to our data. Variant chr10-74083342-T-A is described in ClinVar as [Benign]. Clinvar id is 498457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-74083342-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.96 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VCL	NM_014000.3	c.875-24T>A		intron_variant		ENST00000211998.10	NP_054706.1
VCL	NM_003373.4	c.875-24T>A		intron_variant			NP_003364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VCL	ENST00000211998.10	c.875-24T>A		intron_variant		1	NM_014000.3	ENSP00000211998

Frequencies

GnomAD3 genomes AF: 0.660 AC: 100388 AN: 152048 Hom.: 34997 Cov.: 32

Gnomad AFR AF: 0.863

Gnomad AMI AF: 0.543

Gnomad AMR AF: 0.589

Gnomad ASJ AF: 0.512

Gnomad EAS AF: 0.982

Gnomad SAS AF: 0.778

Gnomad FIN AF: 0.653

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.532

Gnomad OTH AF: 0.608

GnomAD3 exomes AF: 0.640 AC: 160777 AN: 251162 Hom.: 54069 AF XY: 0.636 AC XY: 86294 AN XY: 135754

Gnomad AFR exome AF: 0.872

Gnomad AMR exome AF: 0.636

Gnomad ASJ exome AF: 0.510

Gnomad EAS exome AF: 0.984

Gnomad SAS exome AF: 0.765

Gnomad FIN exome AF: 0.644

Gnomad NFE exome AF: 0.532

Gnomad OTH exome AF: 0.594

GnomAD4 exome AF: 0.578 AC: 844096 AN: 1459288 Hom.: 252505 Cov.: 34 AF XY: 0.582 AC XY: 422335 AN XY: 726082

Gnomad4 AFR exome AF: 0.876

Gnomad4 AMR exome AF: 0.633

Gnomad4 ASJ exome AF: 0.508

Gnomad4 EAS exome AF: 0.989

Gnomad4 SAS exome AF: 0.757

Gnomad4 FIN exome AF: 0.646

Gnomad4 NFE exome AF: 0.536

Gnomad4 OTH exome AF: 0.601

GnomAD4 genome AF: 0.660 AC: 100504 AN: 152166 Hom.: 35053 Cov.: 32 AF XY: 0.668 AC XY: 49680 AN XY: 74398

Gnomad4 AFR AF: 0.863

Gnomad4 AMR AF: 0.590

Gnomad4 ASJ AF: 0.512

Gnomad4 EAS AF: 0.982

Gnomad4 SAS AF: 0.776

Gnomad4 FIN AF: 0.653

Gnomad4 NFE AF: 0.532

Gnomad4 OTH AF: 0.611

Alfa AF: 0.585 Hom.: 5007

Bravo AF: 0.664

Asia WGS AF: 0.867 AC: 3013 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 14, 2016	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 13, 2022	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	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. -

Dilated cardiomyopathy 1W Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Hypertrophic cardiomyopathy 15 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	15
DANN	Benign	0.77
BranchPoint Hunter		3.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1908339; hg19: chr10-75843100;