rs1554939194

Positions:

• chr10-67180508-G-T

Variant summary

Our verdict is Likely benign. Variant got -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. 15/21 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

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTNNA3	NM_013266.4	c.856C>A	p.Leu286Met	missense_variant	7/18	ENST00000433211.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTNNA3	ENST00000433211.7	c.856C>A	p.Leu286Met	missense_variant	7/18	1	NM_013266.4	P1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 13 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 08, 2017

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a CTNNA3-related disease. This sequence change replaces leucine with methionine at codon 286 of the CTNNA3 protein (p.Leu286Met). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and methionine. -

Computational scores

Source: dbNSFP v4.3

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;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.096
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.66	T;T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.77	N;.
MutationTaster	Benign	0.59	N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.91	N;.
REVEL	Benign	0.21
Sift	Benign	0.87	T;.
Sift4G	Benign	0.96	T;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
Varity_R		0.046
gMVP		0.21

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554939194; hg19: chr10-68940266;