chr3-41224633-A-G

Position:

chr3-41224633-A-G

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP2PP5_Very_Strong

The ENST00000349496.11(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. T41N) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

CTNNB1
ENST00000349496.11 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:5U:1O:2

Conservation

PhyloP100: 9.32

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in ENST00000349496.11

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 id is 17587.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CTNNB1. . Gene score misZ 3.846 (greater than the threshold 3.09). Trascript score misZ 5.712 (greater than threshold 3.09). GenCC has associacion of gene with severe intellectual disability-progressive spastic diplegia syndrome, exudative vitreoretinopathy, exudative vitreoretinopathy 7.

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 id is 17580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTNNB1	NM_001904.4 linkuse as main transcript	c.121A>G	p.Thr41Ala	missense_variant	3/15	ENST00000349496.11	NP_001895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTNNB1	ENST00000349496.11 linkuse as main transcript	c.121A>G	p.Thr41Ala	missense_variant	3/15	1	NM_001904.4	ENSP00000344456	P4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5Uncertain:1Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Likely pathogenic, no assertion criteria provided	literature only	Richard Lifton Laboratory, Yale University School of Medicine	-	- -
Uncertain significance, flagged submission	literature only	Richard Lifton Laboratory, Yale University School of Medicine	-	- -

Hepatoblastoma

Pathogenic:1Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 1999	- -
other, no assertion criteria provided	clinical testing	Donald Williams Parsons Laboratory, Baylor College of Medicine	May 01, 2016	- 2: Mutations in members of targetable cancer pathways, gene families, or functional groups, regardless of tumor type;

Desmoid tumor caused by somatic mutation

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 1999

- -

Desmoid tumor

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Jul 18, 2019

- -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

PM2_Supporting+PS4+PP2 -

Atypical endometrial hyperplasia

Other:1

association, no assertion criteria provided

research

Martignetti Lab, Icahn School of Medicine at Mount Sinai

- -

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

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

MutationTaster

Benign

1.0

D;D;D;D;D

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

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