NM_014000.3:c.875-24T>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.867

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. 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 rank	MANE	Protein	UniProt
VCL	NM_014000.3 link	c.875-24T>A		intron_variant	Intron 7 of 21	ENST00000211998.10	NP_054706.1	P18206-1V9HWK2B3KXA2
VCL	NM_003373.4 link	c.875-24T>A		intron_variant	Intron 7 of 20		NP_003364.1	P18206-2A0A024QZN4B3KXA2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCL	ENST00000211998.10 link	c.875-24T>A		intron_variant	Intron 7 of 21	1	NM_014000.3	ENSP00000211998.5		P18206-1

Frequencies

GnomAD3 genomes

AF:

0.660

AC:

100388

AN:

152048

Hom.:

34997

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.582

AC XY:

422335

AN XY:

726082

show subpopulations

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.:

AF XY:

0.668

AC XY:

49680

AN XY:

74398

show subpopulations

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

LINK: link

Submissions by phenotype

not specified

Benign:4

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 14, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 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. -

Sep 13, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1W

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 15

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over