Genetic Variant CTNNAL1:p.Thr424Ala (chr9-108972752-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003798.4(CTNNAL1):c.1270A>G(p.Thr424Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000661 in 151,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. T424S) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Consequence

CTNNAL1
NM_003798.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.54

Variant links:

Genes affected

CTNNAL1 (HGNC:2512): (catenin alpha like 1) Predicted to enable actin filament binding activity and cadherin binding activity. Acts upstream of or within Rho protein signal transduction. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

CTNNAL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.054238886).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTNNAL1	NM_003798.4 link	c.1270A>G	p.Thr424Ala	missense_variant	Exon 9 of 19	ENST00000325551.9	NP_003789.1	Q9UBT7-1B3KMX6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CTNNAL1	ENST00000325551.9 link	c.1270A>G	p.Thr424Ala	missense_variant	Exon 9 of 19	1	NM_003798.4	ENSP00000320434.4	Q9UBT7-1
CTNNAL1	ENST00000374595.8 link	c.1270A>G	p.Thr424Ala	missense_variant	Exon 9 of 19	1		ENSP00000363723.4	Q9UBT7-2
CTNNAL1	ENST00000488130.1 link	n.541A>G		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.00000661

AC:

AN:

151324

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000661

AC:

AN:

151324

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73798

show subpopulations

Gnomad4 AFR

AF:

0.0000243

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1270A>G (p.T424A) alteration is located in exon 9 (coding exon 9) of the CTNNAL1 gene. This alteration results from a A to G substitution at nucleotide position 1270, causing the threonine (T) at amino acid position 424 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.012

.;T

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.084

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.79

T;T

M_CAP

Benign

0.0028

MetaRNN

Benign

0.054

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.44

N;N

PrimateAI

Benign

0.43

PROVEAN

Benign

0.44

N;N

REVEL

Benign

0.090

Sift

Benign

0.89

T;T

Sift4G

Benign

0.87

T;T

Polyphen

0.0

B;B

Vest4

0.073

MutPred

0.34

Gain of loop (P = 0.002);Gain of loop (P = 0.002);

MVP

0.17

MPC

0.12

ClinPred

0.88

GERP RS

6.0

Varity_R

0.029

gMVP

0.078

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over