rs140913916

Variant names:

• chr10-66520695-T-A
• rs140913916
• NM_013266.4:c.1453A>T

Your query was ambiguous. Multiple possible variants found:

• chr10-66520695-T-A
• chr10-66520695-T-C
• chr10-66520695-T-G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_013266.4(CTNNA3):​c.1453A>T​(p.Thr485Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 1,612,506 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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. T485T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0016 (4 hom.)
• Consequence: CTNNA3 NM_013266.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.85
• Publications: 6 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

ENSG00000298814 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.037484378).
• BP6: Variant 10-66520695-T-A is Benign according to our data. Variant chr10-66520695-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 415361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 194 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.1453A>T	p.Thr485Ser	missense	Exon 11 of 18	NP_037398.2	Q9UI47-1
	CTNNA3	NM_001127384.3		c.1453A>T	p.Thr485Ser	missense	Exon 11 of 18	NP_001120856.1	Q9UI47-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNNA3	ENST00000433211.7	TSL:1 MANE Select	c.1453A>T	p.Thr485Ser	missense	Exon 11 of 18	ENSP00000389714.1	Q9UI47-1
	CTNNA3	ENST00000682758.1		c.1453A>T	p.Thr485Ser	missense	Exon 12 of 19	ENSP00000508047.1	Q9UI47-1
	CTNNA3	ENST00000684154.1		c.1453A>T	p.Thr485Ser	missense	Exon 11 of 18	ENSP00000508371.1	Q9UI47-1

Frequencies

GnomAD3 genomes AF: 0.00127 AC: 194 AN: 152182 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00163

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00127 AC: 317 AN: 249278 AF XY: 0.00133

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.00177

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.00177

Gnomad OTH exome AF: 0.00216

GnomAD4 exome AF: 0.00162 AC: 2372 AN: 1460206 Hom.: 4 Cov.: 30 AF XY: 0.00159 AC XY: 1157 AN XY: 726398

African (AFR) AF: 0.000240 AC: 8 AN: 33372

American (AMR) AF: 0.00173 AC: 77 AN: 44508

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39566

South Asian (SAS) AF: 0.000349 AC: 30 AN: 86014

European-Finnish (FIN) AF: 0.00140 AC: 75 AN: 53394

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5762

European-Non Finnish (NFE) AF: 0.00188 AC: 2086 AN: 1111184

Other (OTH) AF: 0.00124 AC: 75 AN: 60314

GnomAD4 genome AF: 0.00127 AC: 194 AN: 152300 Hom.: 0 Cov.: 31 AF XY: 0.00137 AC XY: 102 AN XY: 74474

African (AFR) AF: 0.000337 AC: 14 AN: 41584

American (AMR) AF: 0.00249 AC: 38 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.00198 AC: 21 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00163 AC: 111 AN: 68018

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00133 Hom.: 0

Bravo AF: 0.00118

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00102 AC: 124

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00279

EpiControl AF: 0.00179

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	2	not specified (2)
-	-	1	Arrhythmogenic right ventricular dysplasia 13 (1)
-	-	1	CTNNA3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	12
DANN	Benign	0.60
DEOGEN2	Benign	0.068	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N
PhyloP100		1.9
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.27	N
REVEL	Benign	0.048
Sift	Benign	0.46	T
Sift4G	Benign	0.72	T
Polyphen		0.28	B
Vest4		0.50
MVP		0.43
MPC		0.084
ClinPred		0.0072	T
GERP RS		4.2
Varity_R		0.050
gMVP		0.17
Mutation Taster		=97/3	polymorphism

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: rs140913916; hg19: chr10-68280453;