rs1060502220

Positions:

• chr5-138924596-A-C
• chr5-138924596-A-G
• chr5-138924596-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001903.5(CTNNA1):​c.1633A>C​(p.Ile545Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. I545T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTNNA1 NM_001903.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.51

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CTNNA1. . Gene score misZ 3.6624 (greater than the threshold 3.09). Trascript score misZ 4.1669 (greater than threshold 3.09). GenCC has associacion of gene with patterned macular dystrophy 2, CTNNA1-related diffuse gastric and lobular breast cancer syndrome, patterned macular dystrophy, hereditary nonpolyposis colon cancer.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTNNA1	NM_001903.5	c.1633A>C	p.Ile545Leu	missense_variant	12/18	ENST00000302763.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTNNA1	ENST00000302763.12	c.1633A>C	p.Ile545Leu	missense_variant	12/18	1	NM_001903.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 23, 2021

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CTNNA1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with leucine at codon 545 of the CTNNA1 protein (p.Ile545Leu). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and leucine. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 18, 2021

The p.I545L variant (also known as c.1633A>C), located in coding exon 11 of the CTNNA1 gene, results from an A to C substitution at nucleotide position 1633. The isoleucine at codon 545 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.040	T;T;T;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;.;D
M_CAP	Benign	0.025	D
MetaRNN	Uncertain	0.63	D;D;D;D
MetaSVM	Benign	-0.38	T
MutationAssessor	Uncertain	2.8	.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.7	.;N;N;N
REVEL	Benign	0.24
Sift	Uncertain	0.0020	.;D;D;D
Sift4G	Uncertain	0.052	T;D;T;T
Polyphen		0.88	P;D;P;.
Vest4		0.66
MutPred		0.69		Loss of catalytic residue at I545 (P = 0.0226);Loss of catalytic residue at I545 (P = 0.0226);Loss of catalytic residue at I545 (P = 0.0226);.;
MVP		0.64
MPC		2.1
ClinPred		0.95	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.71
gMVP		0.82

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-138260285;