rs797044875

chr3-41235763-G-Achr3-41235763-G-C

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001904.4(CTNNB1):c.1723G>A(p.Gly575Arg) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTNNB1 NM_001904.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 10.0

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 15 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, 0.874
• PP5: Variant 3-41235763-G-A is Pathogenic according to our data. Variant chr3-41235763-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208674.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-41235763-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTNNB1	NM_001904.4	c.1723G>A	p.Gly575Arg	missense_variant	11/15	ENST00000349496.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTNNB1	ENST00000349496.11	c.1723G>A	p.Gly575Arg	missense_variant	11/15	1	NM_001904.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 05, 2014

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 04, 2021

For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CTNNB1 protein function. ClinVar contains an entry for this variant (Variation ID: 208674). This missense change has been observed in individual(s) with CTNNB1-related conditions (PMID: 33350591). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 575 of the CTNNB1 protein (p.Gly575Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. -

Severe intellectual disability-progressive spastic diplegia syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Feb 02, 2022

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with exudative vitreoretinopathy 7 (EVR; MIM#617572) and neurodevelopmental disorder with spastic diplegia and visual defects (MIM#615075). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported de novo in least two individuals described to have autism spectrum disorder and neurodevelopmental disorder, respectively (PMID: 28330790, 33350591). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	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	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.87	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	3.4	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	0.93	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		0.98, 0.98, 0.98, 0.98
MutPred		0.60		Gain of MoRF binding (P = 0.0175);Gain of MoRF binding (P = 0.0175);.;Gain of MoRF binding (P = 0.0175);Gain of MoRF binding (P = 0.0175);Gain of MoRF binding (P = 0.0175);Gain of MoRF binding (P = 0.0175);Gain of MoRF binding (P = 0.0175);.;Gain of MoRF binding (P = 0.0175);Gain of MoRF binding (P = 0.0175);.;.;Gain of MoRF binding (P = 0.0175);Gain of MoRF binding (P = 0.0175);Gain of MoRF binding (P = 0.0175);.;.;.;.;Gain of MoRF binding (P = 0.0175);Gain of MoRF binding (P = 0.0175);.;Gain of MoRF binding (P = 0.0175);.;Gain of MoRF binding (P = 0.0175);.;.;Gain of MoRF binding (P = 0.0175);Gain of MoRF binding (P = 0.0175);.;Gain of MoRF binding (P = 0.0175);Gain of MoRF binding (P = 0.0175);Gain of MoRF binding (P = 0.0175);.;Gain of MoRF binding (P = 0.0175);Gain of MoRF binding (P = 0.0175);Gain of MoRF binding (P = 0.0175);Gain of MoRF binding (P = 0.0175);Gain of MoRF binding (P = 0.0175);
MVP		0.95
MPC		2.5
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs797044875; hg19: chr3-41277254; COSMIC: COSV62690253; COSMIC: COSV62690253;