3-41224069-A-G

Position:

• chr3-41224069-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTNNB1	NM_001904.4	c.1A>G	p.Met1?	start_lost	2/15	ENST00000349496.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTNNB1	ENST00000349496.11	c.1A>G	p.Met1?	start_lost	2/15	1	NM_001904.4	P4

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

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 15, 2021

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
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
MutationTaster	Benign	0.92	D;D;D;D;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;