rs61737718

chr10-66379229-G-Achr10-66379229-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_013266.4(CTNNA3):c.1655C>T(p.Thr552Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0045 in 1,614,032 control chromosomes in the GnomAD database, including 273 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T552R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.024 (129 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (144 hom.)
• Consequence: CTNNA3 NM_013266.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.94

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002832234).
• BP6: Variant 10-66379229-G-A is Benign according to our data. Variant chr10-66379229-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 415374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-66379229-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0806 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTNNA3	NM_013266.4	c.1655C>T	p.Thr552Met	missense_variant	12/18	ENST00000433211.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTNNA3	ENST00000433211.7	c.1655C>T	p.Thr552Met	missense_variant	12/18	1	NM_013266.4	P1

Frequencies

GnomAD3 genomes AF: 0.0237 AC: 3609 AN: 152080 Hom.: 129 Cov.: 33

Gnomad AFR AF: 0.0831

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00649

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.00607 AC: 1524 AN: 251172 Hom.: 56 AF XY: 0.00444 AC XY: 603 AN XY: 135726

Gnomad AFR exome AF: 0.0818

Gnomad AMR exome AF: 0.00353

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00103

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00250 AC: 3653 AN: 1461834 Hom.: 144 Cov.: 31 AF XY: 0.00214 AC XY: 1554 AN XY: 727226

Gnomad4 AFR exome AF: 0.0858

Gnomad4 AMR exome AF: 0.00407

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.000453

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000221

Gnomad4 OTH exome AF: 0.00479

GnomAD4 genome AF: 0.0237 AC: 3610 AN: 152198 Hom.: 129 Cov.: 33 AF XY: 0.0224 AC XY: 1670 AN XY: 74424

Gnomad4 AFR AF: 0.0829

Gnomad4 AMR AF: 0.00648

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00155

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.00379 Hom.: 27

Bravo AF: 0.0270

ESP6500AA AF: 0.0851 AC: 375

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00772 AC: 937

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 29, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

CTNNA3-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 01, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Arrhythmogenic right ventricular dysplasia 13 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 18, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	23
Dann	Uncertain	0.97
DEOGEN2	Benign	0.087	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.038
Sift	Benign	0.16	T
Sift4G	Benign	0.18	T
Polyphen		0.0040	B
Vest4		0.33
MVP		0.44
MPC		0.022
ClinPred		0.0090	T
GERP RS		3.7
Varity_R		0.027
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs61737718; hg19: chr10-68138987; COSMIC: COSV65553215;