rs1554939194

Variant names:

• chr10-67180508-G-T
• rs1554939194
• NM_013266.4:c.856C>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_013266.4(CTNNA3):​c.856C>A​(p.Leu286Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,460,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: CTNNA3 NM_013266.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.171
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2455486).
• BS2: High AC in GnomAdExome4 at 15 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNNA3	NM_013266.4	MANE Select	c.856C>A	p.Leu286Met	missense	Exon 7 of 18	NP_037398.2	Q9UI47-1
	CTNNA3	NM_001127384.3		c.856C>A	p.Leu286Met	missense	Exon 7 of 18	NP_001120856.1	Q9UI47-1
	CTNNA3	NM_001291133.2		c.892C>A	p.Leu298Met	missense	Exon 8 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.856C>A	p.Leu286Met	missense	Exon 7 of 18	ENSP00000389714.1	Q9UI47-1
	CTNNA3	ENST00000682758.1		c.856C>A	p.Leu286Met	missense	Exon 8 of 19	ENSP00000508047.1	Q9UI47-1
	CTNNA3	ENST00000684154.1		c.856C>A	p.Leu286Met	missense	Exon 7 of 18	ENSP00000508371.1	Q9UI47-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1460842 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 726788

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111174

Other (OTH) AF: 0.00 AC: 0 AN: 60346

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Arrhythmogenic right ventricular dysplasia 13 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	18
DANN	Benign	0.93
DEOGEN2	Benign	0.050	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.096
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.77	N
PhyloP100		0.17
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.91	N
REVEL	Benign	0.21
Sift	Benign	0.87	T
Sift4G	Benign	0.96	T
Polyphen		0.78	P
Vest4		0.42
MutPred		0.67		Gain of relative solvent accessibility (P = 0.0522)
MVP		0.43
MPC		0.15
ClinPred		0.83	D
GERP RS		2.3
PromoterAI		-0.0016	Neutral
Varity_R		0.046
gMVP		0.21
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1554939194; hg19: chr10-68940266;