rs61737718

Positions:

Variant summary

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

The NM_013266.4(CTNNA3):c.1655C>T(p.Thr552Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0045 in 1,614,032 control chromosomes in the GnomAD database, including 273 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict 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. T552R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.024 ( 129 hom., cov: 33)

Exomes 𝑓: 0.0025 ( 144 hom. )

Consequence

CTNNA3
NM_013266.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.94

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002832234).

BP6

Variant 10-66379229-G-A is Benign according to our data. Variant chr10-66379229-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 415374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-66379229-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0806 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTNNA3	NM_013266.4 linkuse as main transcript	c.1655C>T	p.Thr552Met	missense_variant	12/18	ENST00000433211.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTNNA3	ENST00000433211.7 linkuse as main transcript	c.1655C>T	p.Thr552Met	missense_variant	12/18	1	NM_013266.4	P1	Q9UI47-1

Frequencies

GnomAD3 genomes

AF:

0.0237

AC:

3609

AN:

152080

Hom.:

129

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0831

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00649

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.0182

GnomAD3 exomes

AF:

0.00607

AC:

1524

AN:

251172

Hom.:

AF XY:

0.00444

AC XY:

603

AN XY:

135726

show subpopulations

Gnomad AFR exome

AF:

0.0818

Gnomad AMR exome

AF:

0.00353

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00103

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000264

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00250

AC:

3653

AN:

1461834

Hom.:

144

Cov.:

AF XY:

0.00214

AC XY:

1554

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.0858

Gnomad4 AMR exome

AF:

0.00407

Gnomad4 ASJ exome

AF:

0.000191

Gnomad4 EAS exome

AF:

0.000453

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000221

Gnomad4 OTH exome

AF:

0.00479

GnomAD4 genome

AF:

0.0237

AC:

3610

AN:

152198

Hom.:

129

Cov.:

AF XY:

0.0224

AC XY:

1670

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.0829

Gnomad4 AMR

AF:

0.00648

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00155

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000323

Gnomad4 OTH

AF:

0.0180

Alfa

AF:

0.00379

Hom.:

Bravo

AF:

0.0270

ESP6500AA

AF:

0.0851

AC:

375

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00772

AC:

937

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 29, 2023	- -
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	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 18, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Jul 01, 2019

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

0.077

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Benign

0.087

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.80

MetaRNN

Benign

0.0028

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.97

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.9

REVEL

Benign

0.038

Sift

Benign

0.16

Sift4G

Benign

0.18

Polyphen

0.0040

Vest4

0.33

MVP

0.44

MPC

0.022

ClinPred

0.0090

GERP RS

3.7

Varity_R

0.027

gMVP

0.25

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