rs147116577

Variant names:

• chr10-67539505-C-G
• rs147116577
• NM_013266.4:c.457G>C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_013266.4(CTNNA3):​c.457G>C​(p.Ala153Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000213 in 1,613,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: CTNNA3 NM_013266.4 missense, splice_region
• Scores: Splicing: ADA: 0.0001153
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 0.452
• Publications: 3 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• congenital heart disease

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06957281).
• BP6: Variant 10-67539505-C-G is Benign according to our data. Variant chr10-67539505-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 180310.
• BS2: High AC in GnomAd4 at 21 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNNA3	NM_013266.4	MANE Select	c.457G>C	p.Ala153Pro	missense splice_region	Exon 4 of 18	NP_037398.2
	CTNNA3	NM_001127384.3		c.457G>C	p.Ala153Pro	missense splice_region	Exon 4 of 18	NP_001120856.1
	CTNNA3	NM_001291133.2		c.493G>C	p.Ala165Pro	missense splice_region	Exon 5 of 9	NP_001278062.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNNA3	ENST00000433211.7	TSL:1 MANE Select	c.457G>C	p.Ala153Pro	missense splice_region	Exon 4 of 18	ENSP00000389714.1
	CTNNA3	ENST00000682758.1		c.457G>C	p.Ala153Pro	missense splice_region	Exon 5 of 19	ENSP00000508047.1
	CTNNA3	ENST00000684154.1		c.457G>C	p.Ala153Pro	missense splice_region	Exon 4 of 18	ENSP00000508371.1

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000312 AC: 78 AN: 249932 AF XY: 0.000267

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000613

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.000221 AC: 323 AN: 1460844 Hom.: 0 Cov.: 30 AF XY: 0.000211 AC XY: 153 AN XY: 726706

African (AFR) AF: 0.0000299 AC: 1 AN: 33430

American (AMR) AF: 0.0000224 AC: 1 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86208

European-Finnish (FIN) AF: 0.000244 AC: 13 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.000259 AC: 288 AN: 1111310

Other (OTH) AF: 0.000315 AC: 19 AN: 60324

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74338

African (AFR) AF: 0.0000241 AC: 1 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68032

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000274 Hom.: 0

Bravo AF: 0.000147

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000436 AC: 53

EpiCase AF: 0.000273

EpiControl AF: 0.000297

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CTNNA3: BP4

Jan 25, 2018

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

p.Ala153Pro (c.457G>C) in Exon 4 of the CTNNA3 gene (NM_013266.3) Chromosome location 10:69299263 C / G Based on the information reviewed below, including the lack of case data and this variant's frequency in population databases, we classify it as a Variant of Uncertain Significance, Probably Benign. The CTNNA3 gene currently has no well-established disease association; however, there is preliminary evidence supporting a correlation with autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) (MedGen UID: 816468). This variant has not previously been reported in the literature in association with disease, according to the Invitae report. This is a conservative amino acid change, resulting in the replacement of a nonpolar Alanine with a nonpolar Proline (that is more sterically constrained). Alanine at this location is poorly conserved across ~100 vertebrate species for which we have data. There are no Likely Pathogenic or Pathogenic variants currently listed in ClinVar within 10 amino acids to either side. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant was reported in 81 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 73 non-Finnish Europeans (for the highest allele frequency: 0.06%), 4 Finns, 2 Latinos, and 2 “Other”. Overall MAF 0.03%. Whiffin et al (2017) proposed that variants with frequency greater than 0.009% are unlikely to be pathogenic for ARVC. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases.

not specified Uncertain:1

Oct 03, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.457G>C (p.A153P) alteration is located in exon 4 (coding exon 3) of the CTNNA3 gene. This alteration results from a G to C substitution at nucleotide position 457, causing the alanine (A) at amino acid position 153 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Arrhythmogenic right ventricular dysplasia 13 Uncertain:1

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 153 of the CTNNA3 protein (p.Ala153Pro). This variant is present in population databases (rs147116577, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with CTNNA3-related conditions. ClinVar contains an entry for this variant (Variation ID: 180310). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Primary familial hypertrophic cardiomyopathy Uncertain:1

Oct 14, 2014

Blueprint Genetics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.098	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.070	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.45
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.12
Sift	Benign	0.24	T
Sift4G	Uncertain	0.0090	D
Polyphen		0.15	B
Vest4		0.53
MVP		0.52
MPC		0.054
ClinPred		0.052	T
GERP RS		1.9
Varity_R		0.20
gMVP		0.44
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.034
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: rs147116577; hg19: chr10-69299263;