chr5-138887639-T-G

Variant names:

• chr5-138887639-T-G
• rs755215402
• NM_001903.5:c.1293T>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001903.5(CTNNA1):​c.1293T>G​(p.Ile431Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,454,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I431V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CTNNA1 NM_001903.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:2
• Conservation: PhyloP100: 1.06
• Publications: 4 publications found

Genes affected

CTNNA1 (HGNC:2509): (catenin alpha 1) This gene encodes a member of the catenin family of proteins that play an important role in cell adhesion process by connecting cadherins located on the plasma membrane to the actin filaments inside the cell. The encoded mechanosensing protein contains three vinculin homology domains and undergoes conformational changes in response to cytoskeletal tension, resulting in the reconfiguration of cadherin-actin filament connections. Certain mutations in this gene cause butterfly-shaped pigment dystrophy. [provided by RefSeq, May 2016]

CTNNA1 Gene-Disease associations (from GenCC):

• CTNNA1-related diffuse gastric and lobular breast cancer syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• patterned macular dystrophy 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• patterned macular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38323146).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTNNA1	NM_001903.5	c.1293T>G	p.Ile431Met	missense_variant	Exon 9 of 18	ENST00000302763.12	NP_001894.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTNNA1	ENST00000302763.12	c.1293T>G	p.Ile431Met	missense_variant	Exon 9 of 18	1	NM_001903.5	ENSP00000304669.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1454496 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 723260

African (AFR) AF: 0.00 AC: 0 AN: 33116

American (AMR) AF: 0.00 AC: 0 AN: 42922

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25902

East Asian (EAS) AF: 0.00 AC: 0 AN: 39494

South Asian (SAS) AF: 0.00 AC: 0 AN: 84094

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109754

Other (OTH) AF: 0.00 AC: 0 AN: 60138

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Patterned macular dystrophy 2 Pathogenic:1

Dec 23, 2024

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Uncertain:1

Aug 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 431 of the CTNNA1 protein (p.Ile431Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with butterfly-shaped pigment dystrophy (PMID: 26691986). ClinVar contains an entry for this variant (Variation ID: 225127). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CTNNA1 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Mar 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I431M variant (also known as c.1293T>G), located in coding exon 8 of the CTNNA1 gene, results from a T to G substitution at nucleotide position 1293. The isoleucine at codon 431 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.038	T;T;T;T;.;T;T;T;.;.;.
Eigen	Benign	0.017
Eigen_PC	Benign	0.026
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.86	D;D;.;D;D;D;D;D;D;D;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.38	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.1	.;L;.;.;.;.;.;.;.;.;.
PhyloP100		1.1
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.6	.;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.17
Sift	Uncertain	0.019	.;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.034	D;D;D;T;D;D;D;D;T;D;D
Polyphen		0.44	B;P;B;.;.;.;.;.;.;.;.
Vest4		0.91
MutPred		0.73		Loss of catalytic residue at L436 (P = 0.0592);Loss of catalytic residue at L436 (P = 0.0592);Loss of catalytic residue at L436 (P = 0.0592);.;.;.;.;.;.;.;.;
MVP		0.73
MPC		1.2
ClinPred		0.74	D
GERP RS		1.4
Varity_R		0.47
gMVP		0.35
Mutation Taster		=9/91	disease causing (ClinVar)

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: rs755215402; hg19: chr5-138223328;