3-41233398-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_001904.4(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 NM_001904.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.32

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a helix (size 14) in uniprot entity CTNB1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001904.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CTNNB1
• 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	UniProt
CTNNB1	NM_001904.4	c.1139A>T	p.Asn380Ile	missense_variant	8/15	ENST00000349496.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTNNB1	ENST00000349496.11	c.1139A>T	p.Asn380Ile	missense_variant	8/15	1	NM_001904.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

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	D
BayesDel_noAF	Uncertain	0.12
Cadd	Pathogenic	29
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	D
M_CAP	Pathogenic	0.33	D
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	D
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	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	D
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

Other links and lift over

dbSNP: rs1553631770; hg19: chr3-41274889;