rs372808360

Positions:

• chr10-66766314-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_013266.4(CTNNA3):​c.1231A>G​(p.Ile411Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000682 in 1,613,850 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I411M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000065 (3 hom.)
• Consequence: CTNNA3 NM_013266.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 4.17

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.044529855).
• BP6: Variant 10-66766314-T-C is Benign according to our data. Variant chr10-66766314-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 220976.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}. Variant chr10-66766314-T-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTNNA3	NM_013266.4	c.1231A>G	p.Ile411Val	missense_variant	9/18	ENST00000433211.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTNNA3	ENST00000433211.7	c.1231A>G	p.Ile411Val	missense_variant	9/18	1	NM_013266.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.0000558 AC: 14 AN: 251094 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135660

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.0000650 AC: 95 AN: 1461672 Hom.: 3 Cov.: 31 AF XY: 0.0000495 AC XY: 36 AN XY: 727128

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00131

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74346

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00115

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000957

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.000102

ExAC AF: 0.0000576 AC: 7

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 13 Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 08, 2024	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 411 of the CTNNA3 protein (p.Ile411Val). This variant is present in population databases (rs372808360, 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: 220976). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CTNNA3 protein function with a negative predictive value of 80%. 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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 07, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	17
DANN	Benign	0.69
DEOGEN2	Benign	0.053	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.58	N
MutationTaster	Benign	0.98	D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.74	N
REVEL	Benign	0.050
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0070	B
Vest4		0.25
MutPred		0.55		Gain of methylation at K412 (P = 0.0568);
MVP		0.29
MPC		0.026
ClinPred		0.032	T
GERP RS		6.2
Varity_R		0.042
gMVP		0.081

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs372808360; hg19: chr10-68526072;