rs61749223

Variant names:

• chr10-67521943-A-T
• rs61749223
• NM_013266.4:c.478T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_013266.4(CTNNA3):​c.478T>A​(p.Ser160Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0245 in 1,612,254 control chromosomes in the GnomAD database, including 600 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S160S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.020 (38 hom., cov: 32)
  • Exomes 𝑓: 0.025 (562 hom.)
• Consequence: CTNNA3 NM_013266.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.09
• Publications: 14 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• congenital heart disease

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0069077313).
• BP6: Variant 10-67521943-A-T is Benign according to our data. Variant chr10-67521943-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 240872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0197 (3000/152256) while in subpopulation SAS AF = 0.0371 (179/4828). AF 95% confidence interval is 0.0326. There are 38 homozygotes in GnomAd4. There are 1537 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3000 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNNA3	NM_013266.4	MANE Select	c.478T>A	p.Ser160Thr	missense	Exon 5 of 18	NP_037398.2	Q9UI47-1
	CTNNA3	NM_001127384.3		c.478T>A	p.Ser160Thr	missense	Exon 5 of 18	NP_001120856.1	Q9UI47-1
	CTNNA3	NM_001291133.2		c.514T>A	p.Ser172Thr	missense	Exon 6 of 9	NP_001278062.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNNA3	ENST00000433211.7	TSL:1 MANE Select	c.478T>A	p.Ser160Thr	missense	Exon 5 of 18	ENSP00000389714.1	Q9UI47-1
	CTNNA3	ENST00000682758.1		c.478T>A	p.Ser160Thr	missense	Exon 6 of 19	ENSP00000508047.1	Q9UI47-1
	CTNNA3	ENST00000684154.1		c.478T>A	p.Ser160Thr	missense	Exon 5 of 18	ENSP00000508371.1	Q9UI47-1

Frequencies

GnomAD3 genomes AF: 0.0197 AC: 3003 AN: 152138 Hom.: 38 Cov.: 32

Gnomad AFR AF: 0.00420

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0251

Gnomad ASJ AF: 0.0311

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0373

Gnomad FIN AF: 0.0303

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0262

Gnomad OTH AF: 0.0225

GnomAD2 exomes AF: 0.0232 AC: 5832 AN: 250916 AF XY: 0.0249

Gnomad AFR exome AF: 0.00320

Gnomad AMR exome AF: 0.0174

Gnomad ASJ exome AF: 0.0327

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0304

Gnomad NFE exome AF: 0.0249

Gnomad OTH exome AF: 0.0243

GnomAD4 exome AF: 0.0250 AC: 36428 AN: 1459998 Hom.: 562 Cov.: 31 AF XY: 0.0256 AC XY: 18578 AN XY: 726344

African (AFR) AF: 0.00299 AC: 100 AN: 33434

American (AMR) AF: 0.0175 AC: 780 AN: 44576

Ashkenazi Jewish (ASJ) AF: 0.0318 AC: 829 AN: 26082

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39686

South Asian (SAS) AF: 0.0412 AC: 3546 AN: 86032

European-Finnish (FIN) AF: 0.0296 AC: 1579 AN: 53370

Middle Eastern (MID) AF: 0.0301 AC: 173 AN: 5756

European-Non Finnish (NFE) AF: 0.0252 AC: 27947 AN: 1110774

Other (OTH) AF: 0.0243 AC: 1467 AN: 60288

GnomAD4 genome AF: 0.0197 AC: 3000 AN: 152256 Hom.: 38 Cov.: 32 AF XY: 0.0206 AC XY: 1537 AN XY: 74444

African (AFR) AF: 0.00419 AC: 174 AN: 41552

American (AMR) AF: 0.0250 AC: 382 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0311 AC: 108 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.0371 AC: 179 AN: 4828

European-Finnish (FIN) AF: 0.0303 AC: 321 AN: 10604

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0262 AC: 1782 AN: 68014

Other (OTH) AF: 0.0218 AC: 46 AN: 2114

Alfa AF: 0.0242 Hom.: 36

Bravo AF: 0.0171

TwinsUK AF: 0.0248 AC: 92

ALSPAC AF: 0.0228 AC: 88

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.0253 AC: 218

ExAC AF: 0.0226 AC: 2740

Asia WGS AF: 0.0130 AC: 45 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	1	Arrhythmogenic right ventricular dysplasia 13 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.071	T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
PhyloP100		4.1
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.13
Sift	Benign	0.073	T
Sift4G	Benign	0.12	T
Polyphen		0.96	D
Vest4		0.15
MPC		0.034
ClinPred		0.029	T
GERP RS		5.2
Varity_R		0.11
gMVP		0.075
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61749223; hg19: chr10-69281701;