rs147116577

Positions:

• chr10-67539505-C-G

Variant summary

Our verdict is Benign. Variant got -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. 15/23 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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 180310.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}. Variant chr10-67539505-C-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTNNA3	NM_013266.4	c.457G>C	p.Ala153Pro	missense_variant, splice_region_variant	4/18	ENST00000433211.7	NP_037398.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTNNA3	ENST00000433211.7	c.457G>C	p.Ala153Pro	missense_variant, splice_region_variant	4/18	1	NM_013266.4	ENSP00000389714.1

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

GnomAD3 exomes AF: 0.000312 AC: 78 AN: 249932 Hom.: 0 AF XY: 0.000267 AC XY: 36 AN XY: 135068

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 SAS 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

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000244

Gnomad4 NFE exome AF: 0.000259

Gnomad4 OTH exome AF: 0.000315

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

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.000478

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

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	CTNNA3: BP4 -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jan 25, 2018	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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2023

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2024

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

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Oct 14, 2014

- -

Computational scores

Source: dbNSFP v4.3

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;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.070	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.12
Sift	Benign	0.24	T;D
Sift4G	Uncertain	0.0090	D;T
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs147116577; hg19: chr10-69299263;