3-41224633-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1PM2PM5PP5_Very_Strong

The NM_001904.4(CTNNB1):c.121A>G(p.Thr41Ala) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T41S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

CTNNB1
NM_001904.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:5U:1O:3

Conservation

PhyloP100: 9.32

Publications

476 publications found

Variant links:

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]

CTNNB1 Gene-Disease associations (from GenCC):

exudative vitreoretinopathy
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
severe intellectual disability-progressive spastic diplegia syndrome
Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Illumina, G2P, Ambry Genetics
exudative vitreoretinopathy 7
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

CTNNB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_001904.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-41224634-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 17587.Status of the report is criteria_provided_single_submitter, 1 stars.

PP5

Variant 3-41224633-A-G is Pathogenic according to our data. Variant chr3-41224633-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 17580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTNNB1	NM_001904.4 link	c.121A>G	p.Thr41Ala	missense_variant	Exon 3 of 15	ENST00000349496.11	NP_001895.1	P35222A0A024R2Q3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CTNNB1	ENST00000349496.11 link	c.121A>G	p.Thr41Ala	missense_variant	Exon 3 of 15	1	NM_001904.4	ENSP00000344456.5	P35222
CTNNB1	ENST00000645982.1 link	c.121A>G	p.Thr41Ala	missense_variant	Exon 3 of 16			ENSP00000494845.1	P35222
CTNNB1	ENST00000715152.1 link	n.121A>G		non_coding_transcript_exon_variant	Exon 3 of 16			ENSP00000520353.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5Uncertain:1Other:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Richard Lifton Laboratory, Yale University School of Medicine

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:literature only

- -

Richard Lifton Laboratory, Yale University School of Medicine

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Hepatoblastoma

Pathogenic:1Other:1

May 01, 2016

Donald Williams Parsons Laboratory, Baylor College of Medicine

Significance:other

Review Status:no assertion criteria provided

Collection Method:clinical testing

- 2: Mutations in members of targetable cancer pathways, gene families, or functional groups, regardless of tumor type;

Sep 01, 1999

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Desmoid tumor caused by somatic mutation

Pathogenic:1

Sep 01, 1999

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Desmoid tumor

Pathogenic:1

Jul 18, 2019

Genetics and Molecular Pathology, SA Pathology

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Medulloblastoma;C0206711:Pilomatrixoma;C0346629:Colorectal cancer;C1140680:Ovarian cancer;C2239176:Hepatocellular carcinoma;C3554449:Severe intellectual disability-progressive spastic diplegia syndrome;C4539767:Exudative vitreoretinopathy 7

Pathogenic:1

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_Supporting+PS4+PP2 -

Neoplasm

Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:-

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Atypical endometrial hyperplasia

Other:1

Martignetti Lab, Icahn School of Medicine at Mount Sinai

Significance:association

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

D;T;D;T;D;D;D;D;D;T;D;D;.;T;D;D;D;T;.;T;T;D;D;.;.;.;D;T;.;D;D;T;D;.;D;T;D;D;D;D;D

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

.;D;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;D;.;.;.;.;T;D;D;.;.;D;.;.;.;.;D;.;D;.;.;.;.;D

M_CAP

Benign

0.059

MetaRNN

Uncertain

0.68

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;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.54

MutationAssessor

Uncertain

2.7

M;.;M;.;M;M;M;M;M;.;M;M;.;.;M;M;M;.;.;.;.;M;M;.;.;.;M;.;.;M;M;.;M;.;M;.;M;M;M;M;M

PhyloP100

9.3

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-5.0

.;D;.;.;D;.;.;.;D;.;D;D;.;.;D;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;D

REVEL

Uncertain

0.40

Sift

Pathogenic

0.0

.;D;.;.;D;.;.;.;D;.;D;D;.;.;D;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;D

Sift4G

Pathogenic

0.0

.;D;.;.;D;.;.;.;D;.;D;D;.;.;D;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;D

Polyphen

0.94

P;.;P;.;P;P;P;P;P;.;P;P;.;.;P;P;P;.;.;.;.;P;P;.;.;.;P;.;.;P;P;.;P;.;P;.;P;P;P;P;P

Vest4

0.72, 0.72, 0.71, 0.73

MutPred

0.28

Loss of glycosylation at T41 (P = 0.0069);.;Loss of glycosylation at T41 (P = 0.0069);.;Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);.;Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);.;.;Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);.;.;.;.;Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);.;Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);.;Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);.;Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);Loss of glycosylation at T41 (P = 0.0069);

MVP

0.78

MPC

2.1

ClinPred

0.99

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.81

gMVP

0.80

Mutation Taster

=1/99

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over