NM_003798.4:c.1270A>G

Variant names:

• chr9-108972752-T-C
• rs1394147240
• NM_003798.4:c.1270A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_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. 16/22 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. T424S) has been classified as Benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: CTNNAL1 NM_003798.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.54
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.054238886).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003798.4. 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
	CTNNAL1	NM_003798.4	MANE Select	c.1270A>G	p.Thr424Ala	missense	Exon 9 of 19	NP_003789.1	Q9UBT7-1
	CTNNAL1	NM_001286974.2		c.1270A>G	p.Thr424Ala	missense	Exon 9 of 19	NP_001273903.1	Q9UBT7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTNNAL1	ENST00000325551.9	TSL:1 MANE Select	c.1270A>G	p.Thr424Ala	missense	Exon 9 of 19	ENSP00000320434.4	Q9UBT7-1
	CTNNAL1	ENST00000374595.8	TSL:1	c.1270A>G	p.Thr424Ala	missense	Exon 9 of 19	ENSP00000363723.4	Q9UBT7-2
	CTNNAL1	ENST00000863428.1		c.1270A>G	p.Thr424Ala	missense	Exon 9 of 19	ENSP00000533487.1

Frequencies

GnomAD3 genomes AF: 0.00000661 AC: 1 AN: 151324 Hom.: 0 Cov.: 31

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.: 32

GnomAD4 genome AF: 0.00000661 AC: 1 AN: 151324 Hom.: 0 Cov.: 31 AF XY: 0.0000136 AC XY: 1 AN XY: 73798

African (AFR) AF: 0.0000243 AC: 1 AN: 41102

American (AMR) AF: 0.00 AC: 0 AN: 15080

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10438

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67986

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.084
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.44	N
PhyloP100		2.5
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.44	N
REVEL	Benign	0.090
Sift	Benign	0.89	T
Sift4G	Benign	0.87	T
Polyphen		0.0	B
Vest4		0.073
MutPred		0.34		Gain of loop (P = 0.002)
MVP		0.17
MPC		0.12
ClinPred		0.88	D
GERP RS		6.0
Varity_R		0.029
gMVP		0.078
Mutation Taster		=94/6	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: rs1394147240; hg19: chr9-111735032;