Variant chr3-41233398-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP2PP3_ModeratePP5_Moderate

The ENST00000349496.11(CTNNB1):c.1139A>T(p.Asn380Ile) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N380K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

CTNNB1
ENST00000349496.11 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P: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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in ENST00000349496.11

PM2

Very rare variant in population databases, with high coverage;

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.899

PP5

Variant 3-41233398-A-T is Pathogenic according to our data. Variant chr3-41233398-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 520788.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTNNB1	NM_001904.4 linkuse as main transcript	c.1139A>T	p.Asn380Ile	missense_variant	8/15	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.1139A>T	p.Asn380Ile	missense_variant	8/15	1	NM_001904.4	ENSP00000344456	P4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 28, 2015

- -

Exudative vitreoretinopathy 7

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Jun 07, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.55

D;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

0.92

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.90

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

Uncertain

0.31

MutationAssessor

Pathogenic

3.0

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

0.89

PROVEAN

Pathogenic

-8.5

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

REVEL

Pathogenic

0.72

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0010

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

Polyphen

1.0

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

Vest4

0.69, 0.69, 0.70, 0.69, 0.70

MutPred

0.65

Gain of catalytic residue at L385 (P = 0.0343);Gain of catalytic residue at L385 (P = 0.0343);.;Gain of catalytic residue at L385 (P = 0.0343);Gain of catalytic residue at L385 (P = 0.0343);Gain of catalytic residue at L385 (P = 0.0343);Gain of catalytic residue at L385 (P = 0.0343);Gain of catalytic residue at L385 (P = 0.0343);.;Gain of catalytic residue at L385 (P = 0.0343);Gain of catalytic residue at L385 (P = 0.0343);.;.;Gain of catalytic residue at L385 (P = 0.0343);Gain of catalytic residue at L385 (P = 0.0343);Gain of catalytic residue at L385 (P = 0.0343);.;.;.;.;Gain of catalytic residue at L385 (P = 0.0343);Gain of catalytic residue at L385 (P = 0.0343);.;Gain of catalytic residue at L385 (P = 0.0343);.;Gain of catalytic residue at L385 (P = 0.0343);.;Gain of catalytic residue at L385 (P = 0.0343);Gain of catalytic residue at L385 (P = 0.0343);Gain of catalytic residue at L385 (P = 0.0343);.;Gain of catalytic residue at L385 (P = 0.0343);Gain of catalytic residue at L385 (P = 0.0343);Gain of catalytic residue at L385 (P = 0.0343);.;Gain of catalytic residue at L385 (P = 0.0343);Gain of catalytic residue at L385 (P = 0.0343);Gain of catalytic residue at L385 (P = 0.0343);Gain of catalytic residue at L385 (P = 0.0343);Gain of catalytic residue at L385 (P = 0.0343);

MVP

0.84

MPC

2.5

ClinPred

1.0

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.96

gMVP

0.98

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

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