rs143682596

Positions:

chr10-66766412-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_013266.4(CTNNA3):c.1133G>A(p.Arg378His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00058 in 1,603,932 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R378C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0023 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00040 ( 3 hom. )

Consequence

CTNNA3
NM_013266.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 7.91

Variant links:

Genes affected

CTNNA3 (HGNC:2511): (catenin alpha 3) This gene encodes a protein that belongs to the vinculin/alpha-catenin family. The encoded protein plays a role in cell-cell adhesion in muscle cells. Mutations in this gene are associated with arrhythmogenic right ventricular dysplasia, familial 13. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

CTNNA3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015002102).

BP6

Variant 10-66766412-C-T is Benign according to our data. Variant chr10-66766412-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 415363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-66766412-C-T is described in Lovd as [Likely_benign]. Variant chr10-66766412-C-T is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 356 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTNNA3	NM_013266.4 linkuse as main transcript	c.1133G>A	p.Arg378His	missense_variant	9/18	ENST00000433211.7	NP_037398.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTNNA3	ENST00000433211.7 linkuse as main transcript	c.1133G>A	p.Arg378His	missense_variant	9/18	1	NM_013266.4	ENSP00000389714	P1	Q9UI47-1

Frequencies

GnomAD3 genomes

AF:

0.00233

AC:

354

AN:

152004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00749

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00240

GnomAD3 exomes

AF:

0.000777

AC:

190

AN:

244422

Hom.:

AF XY:

0.000758

AC XY:

100

AN XY:

131950

show subpopulations

Gnomad AFR exome

AF:

0.00643

Gnomad AMR exome

AF:

0.000747

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000552

Gnomad SAS exome

AF:

0.00170

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000631

Gnomad OTH exome

AF:

0.000676

GnomAD4 exome

AF:

0.000396

AC:

575

AN:

1451812

Hom.:

Cov.:

AF XY:

0.000409

AC XY:

295

AN XY:

721584

show subpopulations

Gnomad4 AFR exome

AF:

0.00764

Gnomad4 AMR exome

AF:

0.000941

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00206

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000515

Gnomad4 OTH exome

AF:

0.000767

GnomAD4 genome

AF:

0.00234

AC:

356

AN:

152120

Hom.:

Cov.:

AF XY:

0.00234

AC XY:

174

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00751

Gnomad4 AMR

AF:

0.00164

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00229

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000433

Hom.:

Bravo

AF:

0.00289

ESP6500AA

AF:

0.00499

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000939

AC:

114

Asia WGS

AF:

0.00115

AC:

AN:

3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 2019	- -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 25, 2024	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Arrhythmogenic right ventricular dysplasia 13

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

CTNNA3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 07, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.29

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.015

MetaSVM

Benign

-0.37

MutationAssessor

Benign

1.9

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.6

REVEL

Uncertain

0.42

Sift

Uncertain

0.0020

Sift4G

Benign

0.094

Polyphen

1.0

Vest4

0.86

MVP

0.84

MPC

0.14

ClinPred

0.011

GERP RS

6.2

Varity_R

0.48

gMVP

0.35

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

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