rs373233387

Positions:

• chr10-67521843-T-A
• chr10-67521843-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_013266.4(CTNNA3):​c.578A>T​(p.Gln193Leu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. 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. Q193R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTNNA3 NM_013266.4 missense, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.92

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 Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTNNA3	NM_013266.4	c.578A>T	p.Gln193Leu	missense_variant, splice_region_variant	5/18	ENST00000433211.7	NP_037398.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTNNA3	ENST00000433211.7	c.578A>T	p.Gln193Leu	missense_variant, splice_region_variant	5/18	1	NM_013266.4	ENSP00000389714	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.49	T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Benign	0.26
Sift	Benign	0.16	T;D
Sift4G	Uncertain	0.057	T;D
Polyphen		0.93	P;.
Vest4		0.69
MutPred		0.60		Loss of ubiquitination at K196 (P = 0.0505);Loss of ubiquitination at K196 (P = 0.0505);
MVP		0.52
MPC		0.036
ClinPred		0.91	D
GERP RS		5.2
Varity_R		0.19
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.87		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.87		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs373233387; hg19: chr10-69281601;