3-41224069-A-G

Variant names:

• chr3-41224069-A-G
• rs956534023
• NM_001904.4:c.1A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The NM_001904.4(CTNNB1):​c.1A>G​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTNNB1 NM_001904.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.46

Genes affected

CTNNB1 (HGNC:2514): (catenin beta 1) The protein encoded by this gene is part of a complex of proteins that constitute adherens junctions (AJs). AJs are necessary for the creation and maintenance of epithelial cell layers by regulating cell growth and adhesion between cells. The encoded protein also anchors the actin cytoskeleton and may be responsible for transmitting the contact inhibition signal that causes cells to stop dividing once the epithelial sheet is complete. Finally, this protein binds to the product of the APC gene, which is mutated in adenomatous polyposis of the colon. Mutations in this gene are a cause of colorectal cancer (CRC), pilomatrixoma (PTR), medulloblastoma (MDB), and ovarian cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 8 codons. Genomic position: 41224534. Lost 0.009 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTNNB1	NM_001904.4	c.1A>G	p.Met1?	start_lost	Exon 2 of 15	ENST00000349496.11	NP_001895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTNNB1	ENST00000349496.11	c.1A>G	p.Met1?	start_lost	Exon 2 of 15	1	NM_001904.4	ENSP00000344456.5
CTNNB1	ENST00000645982.1	c.1A>G	p.Met1?	start_lost	Exon 2 of 16			ENSP00000494845.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

CTNNB1-related syndromic intellectual disability Uncertain:1

Jan 15, 2021

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CTNNB1 c.1A>G (p.Met1?) variant is predicted to disrupt the initiator codon and thus potentially may interfere with protein expression. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. This variant is not found in the in the Genome Aggregation Database, in a region of good sequence coverage, suggesting that the variant is rare. Based on the limited evidence, the p.Met1? variant is classified as a variant of uncertain significance for CTNNB1-related syndromic intellectual disability. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.34	T;T;T;T;T;T;T;T;T;T;T;T;T;T;.;.;.;T;.;T;T;T;.;T;T;T;T;T;T
Eigen	Benign	0.079
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;D;D;.;D;.;.;.;D;.;.;.;.;.;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.97	T
PROVEAN	Benign	0.010	.;.;N;.;D;.;N;N;N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N;.;.;N
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	.;.;D;.;.;.;D;D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;D
Sift4G	Benign	0.33	.;.;T;.;.;.;T;T;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;D
Polyphen		0.0060	B;B;B;B;B;B;B;B;B;B;B;B;B;B;.;.;.;B;.;B;B;B;.;B;B;B;B;B;B
Vest4		0.93, 0.93, 0.93, 0.93
MutPred		0.98		Gain of catalytic residue at M1 (P = 0.071);Gain of catalytic residue at M1 (P = 0.071);Gain of catalytic residue at M1 (P = 0.071);Gain of catalytic residue at M1 (P = 0.071);Gain of catalytic residue at M1 (P = 0.071);Gain of catalytic residue at M1 (P = 0.071);Gain of catalytic residue at M1 (P = 0.071);Gain of catalytic residue at M1 (P = 0.071);Gain of catalytic residue at M1 (P = 0.071);Gain of catalytic residue at M1 (P = 0.071);Gain of catalytic residue at M1 (P = 0.071);Gain of catalytic residue at M1 (P = 0.071);Gain of catalytic residue at M1 (P = 0.071);Gain of catalytic residue at M1 (P = 0.071);Gain of catalytic residue at M1 (P = 0.071);Gain of catalytic residue at M1 (P = 0.071);Gain of catalytic residue at M1 (P = 0.071);Gain of catalytic residue at M1 (P = 0.071);Gain of catalytic residue at M1 (P = 0.071);Gain of catalytic residue at M1 (P = 0.071);Gain of catalytic residue at M1 (P = 0.071);Gain of catalytic residue at M1 (P = 0.071);Gain of catalytic residue at M1 (P = 0.071);Gain of catalytic residue at M1 (P = 0.071);Gain of catalytic residue at M1 (P = 0.071);Gain of catalytic residue at M1 (P = 0.071);Gain of catalytic residue at M1 (P = 0.071);Gain of catalytic residue at M1 (P = 0.071);Gain of catalytic residue at M1 (P = 0.071);
MVP		0.92
ClinPred		0.84	D
GERP RS		5.6
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.72
gMVP		0.76

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

Other links and lift over

dbSNP: rs956534023; hg19: chr3-41265560;