chr10-67539564-G-C

Variant names:

• chr10-67539564-G-C
• rs763257801
• NM_013266.4:c.398C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_013266.4(CTNNA3):​c.398C>G​(p.Thr133Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T133M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CTNNA3 NM_013266.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.22
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• arrhythmogenic right ventricular dysplasia 13

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• congenital heart disease

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.862
• BS2: High AC in GnomAdExome4 at 8 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013266.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNNA3	NM_013266.4	MANE Select	c.398C>G	p.Thr133Arg	missense	Exon 4 of 18	NP_037398.2
	CTNNA3	NM_001127384.3		c.398C>G	p.Thr133Arg	missense	Exon 4 of 18	NP_001120856.1
	CTNNA3	NM_001291133.2		c.434C>G	p.Thr145Arg	missense	Exon 5 of 9	NP_001278062.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNNA3	ENST00000433211.7	TSL:1 MANE Select	c.398C>G	p.Thr133Arg	missense	Exon 4 of 18	ENSP00000389714.1
	CTNNA3	ENST00000682758.1		c.398C>G	p.Thr133Arg	missense	Exon 5 of 19	ENSP00000508047.1
	CTNNA3	ENST00000684154.1		c.398C>G	p.Thr133Arg	missense	Exon 4 of 18	ENSP00000508371.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250642 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461562 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727090

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111796

Other (OTH) AF: 0.0000166 AC: 1 AN: 60366

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T133R variant (also known as c.398C>G), located in coding exon 3 of the CTNNA3 gene, results from a C to G substitution at nucleotide position 398. The threonine at codon 133 is replaced by arginine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.9	L
PhyloP100		8.2
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.67		Gain of MoRF binding (P = 0.0143)
MVP		0.68
MPC		0.15
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.83
gMVP		0.73
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs763257801; hg19: chr10-69299322;