10-74114909-A-T

Position:

• chr10-74114909-A-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_014000.3(VCL):​c.3258+10A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00319 in 1,578,654 control chromosomes in the GnomAD database, including 19 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 0.0026 (4 hom., cov: 29)
  • Exomes 𝑓: 0.0033 (15 hom.)
• Consequence: VCL NM_014000.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: -0.0930

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 10-74114909-A-T is Benign according to our data. Variant chr10-74114909-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45609.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1, Benign=6}. Variant chr10-74114909-A-T is described in Lovd as [Benign]. Variant chr10-74114909-A-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 392 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VCL	NM_014000.3	c.3258+10A>T		intron_variant		ENST00000211998.10	NP_054706.1
VCL	NM_003373.4	c.3054+10A>T		intron_variant			NP_003364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VCL	ENST00000211998.10	c.3258+10A>T		intron_variant		1	NM_014000.3	ENSP00000211998.5
VCL	ENST00000372755.7	c.3054+10A>T		intron_variant		1		ENSP00000361841.3
VCL	ENST00000623461.3	n.5857+10A>T		intron_variant		1
VCL	ENST00000624354.3	n.*3013+10A>T		intron_variant		2		ENSP00000485551.1

Frequencies

GnomAD3 genomes AF: 0.00259 AC: 392 AN: 151388 Hom.: 4 Cov.: 29

Gnomad AFR AF: 0.000583

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00224

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000425

Gnomad FIN AF: 0.00209

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00428

Gnomad OTH AF: 0.00386

GnomAD3 exomes AF: 0.00269 AC: 517 AN: 192474 Hom.: 3 AF XY: 0.00262 AC XY: 268 AN XY: 102234

Gnomad AFR exome AF: 0.000826

Gnomad AMR exome AF: 0.00204

Gnomad ASJ exome AF: 0.000670

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00104

Gnomad FIN exome AF: 0.00273

Gnomad NFE exome AF: 0.00441

Gnomad OTH exome AF: 0.00218

GnomAD4 exome AF: 0.00326 AC: 4648 AN: 1427148 Hom.: 15 Cov.: 31 AF XY: 0.00320 AC XY: 2263 AN XY: 706498

Gnomad4 AFR exome AF: 0.000454

Gnomad4 AMR exome AF: 0.00180

Gnomad4 ASJ exome AF: 0.000944

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00108

Gnomad4 FIN exome AF: 0.00305

Gnomad4 NFE exome AF: 0.00379

Gnomad4 OTH exome AF: 0.00248

GnomAD4 genome AF: 0.00259 AC: 392 AN: 151506 Hom.: 4 Cov.: 29 AF XY: 0.00237 AC XY: 175 AN XY: 73974

Gnomad4 AFR AF: 0.000581

Gnomad4 AMR AF: 0.00224

Gnomad4 ASJ AF: 0.000866

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000425

Gnomad4 FIN AF: 0.00209

Gnomad4 NFE AF: 0.00429

Gnomad4 OTH AF: 0.00382

Alfa AF: 0.00301 Hom.: 0

Bravo AF: 0.00227

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 13, 2011	3258+10A>T in Intron 21 of VCL: This variant is not expected to have clinical si gnificance because it is not located within the splice consensus sequence and ha s been identified in 0.4% (28/7018) of European American chromosomes from a broa d population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu /EVS; dbSNP rs71579379). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 18, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 26, 2018	Variant summary: VCL c.3258+10A>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0027 in 217628 control chromosomes, predominantly within the Non-Finnish European subpopulation at a frequency of 0.0045 in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 180 fold above the estimated maximal expected allele frequency for a pathogenic variant in VCL causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.3258+10A>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as benign/likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Dilated cardiomyopathy 1W Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	VCL: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Nov 08, 2019

- -

Primary dilated cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.2
DANN	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs71579379; hg19: chr10-75874667;