10-66280622-C-T

Variant names:

• chr10-66280622-C-T
• rs193155648
• NM_013266.4:c.1733-1G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 8P and 4B. PVS1 BS2

The NM_013266.4(CTNNA3):​c.1733-1G>A variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000414 in 1,449,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CTNNA3 NM_013266.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.75
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• BS2: High AC in GnomAdExome4 at 6 Unknown,AD 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.1733-1G>A		splice_acceptor intron	N/A	NP_037398.2	Q9UI47-1
	CTNNA3	NM_001127384.3		c.1733-1G>A		splice_acceptor intron	N/A	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.1733-1G>A		splice_acceptor intron	N/A	ENSP00000389714.1	Q9UI47-1
	CTNNA3	ENST00000682758.1		c.1733-1G>A		splice_acceptor intron	N/A	ENSP00000508047.1	Q9UI47-1
	CTNNA3	ENST00000684154.1		c.1733-1G>A		splice_acceptor intron	N/A	ENSP00000508371.1	Q9UI47-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000414 AC: 6 AN: 1449316 Hom.: 0 Cov.: 29 AF XY: 0.00000277 AC XY: 2 AN XY: 721428

African (AFR) AF: 0.00 AC: 0 AN: 32654

American (AMR) AF: 0.00 AC: 0 AN: 43446

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25854

East Asian (EAS) AF: 0.00 AC: 0 AN: 39284

South Asian (SAS) AF: 0.00 AC: 0 AN: 84976

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50842

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5278

European-Non Finnish (NFE) AF: 0.00000452 AC: 5 AN: 1107114

Other (OTH) AF: 0.0000167 AC: 1 AN: 59868

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		5.7
GERP RS		5.9
Mutation Taster		=11/89	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.99		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs193155648; hg19: chr10-68040380;