chr10-67180508-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

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

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.171
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]

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ACMG classification

Classification made for transcript

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
CTNNA3NM_013266.4 linkuse as main transcriptc.856C>A p.Leu286Met missense_variant 7/18 ENST00000433211.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CTNNA3ENST00000433211.7 linkuse as main transcriptc.856C>A p.Leu286Met missense_variant 7/181 NM_013266.4 P1Q9UI47-1

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
show subpopulations
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
LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 13 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeNov 08, 2017In 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1554939194; hg19: chr10-68940266; API