10-67539510-A-T

Variant names:

• chr10-67539510-A-T
• rs756167695
• NM_013266.4:c.452T>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_013266.4(CTNNA3):​c.452T>A​(p.Val151Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V151G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTNNA3 NM_013266.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.67
• Publications: 1 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• congenital heart disease

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNNA3	NM_013266.4	MANE Select	c.452T>A	p.Val151Glu	missense	Exon 4 of 18	NP_037398.2	Q9UI47-1
	CTNNA3	NM_001127384.3		c.452T>A	p.Val151Glu	missense	Exon 4 of 18	NP_001120856.1	Q9UI47-1
	CTNNA3	NM_001291133.2		c.488T>A	p.Val163Glu	missense	Exon 5 of 9	NP_001278062.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNNA3	ENST00000433211.7	TSL:1 MANE Select	c.452T>A	p.Val151Glu	missense	Exon 4 of 18	ENSP00000389714.1	Q9UI47-1
	CTNNA3	ENST00000682758.1		c.452T>A	p.Val151Glu	missense	Exon 5 of 19	ENSP00000508047.1	Q9UI47-1
	CTNNA3	ENST00000684154.1		c.452T>A	p.Val151Glu	missense	Exon 4 of 18	ENSP00000508371.1	Q9UI47-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250114 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: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.34	N
PhyloP100		7.7
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.77	P
Vest4		0.73
MutPred		0.68		Gain of disorder (P = 0.034)
MVP		0.64
MPC		0.13
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.78
gMVP		0.36
Mutation Taster		=74/26	polymorphism

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

Other links and lift over

dbSNP: rs756167695; hg19: chr10-69299268;