rs41274090

Positions:

Variant summary

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

The NM_013266.4(CTNNA3):c.1603C>T(p.Arg535Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0123 in 1,614,046 control chromosomes in the GnomAD database, including 205 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. R535H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.010 ( 14 hom., cov: 33)

Exomes 𝑓: 0.013 ( 191 hom. )

Consequence

CTNNA3
NM_013266.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 4.75

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=0.009424508).

BP6

Variant 10-66379281-G-A is Benign according to our data. Variant chr10-66379281-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 240864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-66379281-G-A is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 1588 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTNNA3	NM_013266.4 linkuse as main transcript	c.1603C>T	p.Arg535Cys	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.1603C>T	p.Arg535Cys	missense_variant	12/18	1	NM_013266.4	P1	Q9UI47-1

Frequencies

GnomAD3 genomes

AF:

0.0104

AC:

1589

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00485

Gnomad AMI

AF:

0.0417

Gnomad AMR

AF:

0.00393

Gnomad ASJ

AF:

0.0683

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00704

Gnomad FIN

AF:

0.00943

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0131

Gnomad OTH

AF:

0.00911

GnomAD3 exomes

AF:

0.0115

AC:

2877

AN:

251076

Hom.:

AF XY:

0.0114

AC XY:

1545

AN XY:

135682

show subpopulations

Gnomad AFR exome

AF:

0.00535

Gnomad AMR exome

AF:

0.00333

Gnomad ASJ exome

AF:

0.0588

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00797

Gnomad FIN exome

AF:

0.0117

Gnomad NFE exome

AF:

0.0133

Gnomad OTH exome

AF:

0.0126

GnomAD4 exome

AF:

0.0125

AC:

18323

AN:

1461780

Hom.:

191

Cov.:

AF XY:

0.0126

AC XY:

9157

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.00523

Gnomad4 AMR exome

AF:

0.00389

Gnomad4 ASJ exome

AF:

0.0606

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00757

Gnomad4 FIN exome

AF:

0.0143

Gnomad4 NFE exome

AF:

0.0127

Gnomad4 OTH exome

AF:

0.0131

GnomAD4 genome

AF:

0.0104

AC:

1588

AN:

152266

Hom.:

Cov.:

AF XY:

0.00991

AC XY:

738

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.00484

Gnomad4 AMR

AF:

0.00393

Gnomad4 ASJ

AF:

0.0683

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00705

Gnomad4 FIN

AF:

0.00943

Gnomad4 NFE

AF:

0.0131

Gnomad4 OTH

AF:

0.00901

Alfa

AF:

0.0139

Hom.:

Bravo

AF:

0.0100

TwinsUK

AF:

0.0143

AC:

ALSPAC

AF:

0.0127

AC:

ESP6500AA

AF:

0.00454

AC:

ESP6500EA

AF:

0.0151

AC:

130

ExAC

AF:

0.0118

AC:

1435

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0141

EpiControl

AF:

0.0106

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 29, 2023	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2020	This variant is associated with the following publications: (PMID: 21254927, 33232181, 32880476) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	CTNNA3: BS1, BS2 -

Arrhythmogenic right ventricular dysplasia 13

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.39

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.25

Eigen

Pathogenic

0.68

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

MetaRNN

Benign

0.0094

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.0

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-4.3

REVEL

Benign

0.21

Sift

Benign

0.22

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.31

MPC

0.024

ClinPred

0.037

GERP RS

5.8

Varity_R

0.25

gMVP

0.42

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