Human Gene Module / Chromosome 10 / CTNNA3

CTNNA3catenin (cadherin-associated protein), alpha 3

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
15 / 19
Rare Variants / Common Variants
27 / 9
Aliases
CTNNA3, RP11-433J16.1,  MGC26194,  MGC75041,  VR22
Associated Syndromes
-
Chromosome Band
10q21.3
Associated Disorders
ADHD, ID
Relevance to Autism

Genetic association has been found between the CTNNA3 gene and autism in two large cohorts (AGRE and ACC) of European ancestry and replicated in two other cohorts (CAP and CART) (Wang et al., 2009). In addition, rare deletions in the CTNNA3 gene have been identified in individuals with ASD (ORoak et al., 2012). As well, genetic association has been found between the CTNNA3 gene and Alzheimer's disease in females (Miyashita et al., 2007).

Molecular Function

cell adhesion

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CTNNA3 (19 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Recent Recommendation Genetic association of CTNNA3 with late-onset Alzheimer's disease in females Miyashita A , et al. (2007) No -
2 Recent Recommendation Alpha-T-catenin (CTNNA3) gene was identified as a risk variant for toluene diisocyanate-induced asthma by genome-wide association analysis Kim SH , et al. (2009) No -
3 Primary Common genetic variants on 5p14.1 associate with autism spectrum disorders Wang K , et al. (2009) Yes -
4 Positive Association A genome-wide linkage and association scan reveals novel loci for autism Weiss LA , et al. (2009) Yes -
5 Support Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations O'Roak BJ , et al. (2012) Yes -
6 Support Epileptic encephalopathies of the Landau-Kleffner and continuous spike and waves during slow-wave sleep types: genomic dissection makes the link with autism Lesca G , et al. (2012) No ADHD
7 Support A discovery resource of rare copy number variations in individuals with autism spectrum disorder Prasad A , et al. (2013) Yes -
8 Support Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder Girirajan S , et al. (2013) Yes -
9 Support Identification of risk genes for autism spectrum disorder through copy number variation analysis in Austrian families Egger G , et al. (2014) Yes -
10 Support Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene panel Brett M , et al. (2014) Yes MCA
11 Recent Recommendation A CTNNA3 compound heterozygous deletion implicates a role for ?T-catenin in susceptibility to autism spectrum disorder Bacchelli E , et al. (2014) Yes ID
12 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
13 Support ?T-catenin in restricted brain cell types and its potential connection to autism Folmsbee SS , et al. (2016) No -
14 Support Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder Krupp DR , et al. (2017) Yes -
15 Support Phenotype-to-genotype approach reveals head-circumference-associated genes in an autism spectrum disorder cohort Wu H , et al. (2019) Yes Macrocephaly
16 Support A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders Suzuki T et al. (2020) Yes -
17 Support - Zhou X et al. (2022) Yes -
18 Support - Wang J et al. (2023) Yes -
19 Support - Cirnigliaro M et al. (2023) Yes -
Rare Variants   (27)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_gain Unknown - - 24643514 Egger G , et al. (2014)
- - copy_number_loss Unknown - Unknown 22738016 Lesca G , et al. (2012)
- - copy_number_loss Unknown - Simplex 23275889 Prasad A , et al. (2013)
- - copy_number_loss Unknown - Unknown 23275889 Prasad A , et al. (2013)
- - copy_number_loss De novo - Simplex 23375656 Girirajan S , et al. (2013)
- - copy_number_gain Unknown - Multiplex 23375656 Girirajan S , et al. (2013)
- - copy_number_loss Familial Maternal Unknown 22738016 Lesca G , et al. (2012)
c.1003A>G p.Ile335Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
- - copy_number_loss Familial Maternal Simplex 22495309 O'Roak BJ , et al. (2012)
- - copy_number_loss Familial Paternal Simplex 22495309 O'Roak BJ , et al. (2012)
c.1020G>A p.Gln340%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
- - copy_number_loss Familial Maternal Simplex 23375656 Girirajan S , et al. (2013)
- - copy_number_loss Familial Paternal Simplex 23375656 Girirajan S , et al. (2013)
- - copy_number_loss Familial Maternal Simplex 25050139 Bacchelli E , et al. (2014)
- - copy_number_loss Familial Paternal Simplex 25050139 Bacchelli E , et al. (2014)
- - copy_number_loss Familial Maternal Unknown 25050139 Bacchelli E , et al. (2014)
- - copy_number_loss Familial Paternal Unknown 25050139 Bacchelli E , et al. (2014)
- - copy_number_loss Familial Maternal Multiplex 23375656 Girirajan S , et al. (2013)
- - copy_number_loss Familial Paternal Multiplex 23375656 Girirajan S , et al. (2013)
- - copy_number_loss Familial Maternal Multiplex 25050139 Bacchelli E , et al. (2014)
c.1128+1G>T - splice_site_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.916G>A p.Ala306Thr missense_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.152G>C p.Arg51Pro missense_variant De novo - Simplex 28867142 Krupp DR , et al. (2017)
c.1921G>A p.Glu641Lys missense_variant De novo - Simplex 32530565 Suzuki T et al. (2020)
c.2042A>G p.Lys681Arg missense_variant Familial Paternal - 24690944 Brett M , et al. (2014)
c.973C>T p.Arg325Ter stop_gained Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.1237_1238del p.Glu413IlefsTer7 frameshift_variant Familial Paternal Simplex 31674007 Wu H , et al. (2019)
Common Variants   (9)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.1281+52623A>G;c.1317+52623A>G;c.498+52623A>G C/T intron_variant - - - 17761686 Miyashita A , et al. (2007)
c.1281+68209C>T;c.1317+68209C>T;c.498+68209C>T A/G intron_variant - - - 17761686 Miyashita A , et al. (2007)
c.1281+70294A>C;c.1317+70294A>C;c.498+70294A>C T/G intron_variant - - - 17761686 Miyashita A , et al. (2007)
c.1282-54120T>C;c.1318-54120T>C;c.499-54120T>C A/G intron_variant - - - 17761686 Miyashita A , et al. (2007)
c.1282-62755A>G;c.1318-62755A>G;c.499-62755A>G T/C intron_variant - - - 17761686 Miyashita A , et al. (2007)
c.1282-67890A>G;c.1318-67890A>G;c.499-67890A>G T/C intron_variant - - - 17761686 Miyashita A , et al. (2007)
c.1282-53255G>A;c.1282-53255G>T;c.1318-53255G>A;c.1318-53255G>T;c.499-53255G>A;c.499-53255G>T C/A intron_variant - - - 17761686 Miyashita A , et al. (2007)
c.579+108697C>T;c.615+108697C>T - intron_variant - - - 19812673 Weiss LA , et al. (2009)
c.580-225C>T;c.616-225C>T;c.-204-225C>T - intron_variant - - - 19404256 Wang K , et al. (2009)
SFARI Gene score
2

Strong Candidate

Evidence for the role of CTNNA3 in autism comes from two studies. In one genome-wide association study, an imputed SNP in the gene was found to be suggestive of association (Wang et al., 2009). In another study, a TDT analysis showed positive association in 318 trios but was not replicated in a second cohort (Weiss et al., 2009).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

Evidence for the role of CTNNA3 in autism comes from two studies. In one genome-wide association study, an imputed SNP in the gene was found to be suggestive of association (Wang et al., 2009). In another study, a TDT analysis showed positive association in 318 trios but was not replicated in a second cohort (Weiss et al., 2009).

7/1/2020
3
icon
3

Decreased from 3 to 3

Description

Evidence for the role of CTNNA3 in autism comes from two studies. In one genome-wide association study, an imputed SNP in the gene was found to be suggestive of association (Wang et al., 2009). In another study, a TDT analysis showed positive association in 318 trios but was not replicated in a second cohort (Weiss et al., 2009).

Reports Added
[A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders2020]
10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Evidence for the role of CTNNA3 in autism comes from two studies. In one genome-wide association study, an imputed SNP in the gene was found to be suggestive of association (Wang et al., 2009). In another study, a TDT analysis showed positive association in 318 trios but was not replicated in a second cohort (Weiss et al., 2009).

Reports Added
[Phenotype-to-genotype approach reveals head-circumference-associated genes in an autism spectrum disorder cohort.2019] [New Scoring Scheme]
10/1/2017
4
icon
4

Decreased from 4 to 4

Description

Evidence for the role of CTNNA3 in autism comes from two studies. In one genome-wide association study, an imputed SNP in the gene was found to be suggestive of association (Wang et al., 2009). In another study, a TDT analysis showed positive association in 318 trios but was not replicated in a second cohort (Weiss et al., 2009).

Reports Added
[Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder.2017]
7/1/2016
4
icon
4

Decreased from 4 to 4

Description

Evidence for the role of CTNNA3 in autism comes from two studies. In one genome-wide association study, an imputed SNP in the gene was found to be suggestive of association (Wang et al., 2009). In another study, a TDT analysis showed positive association in 318 trios but was not replicated in a second cohort (Weiss et al., 2009).

Reports Added
[T-catenin in restricted brain cell types and its potential connection to autism.2016]
1/1/2016
4
icon
4

Decreased from 4 to 4

Description

Evidence for the role of CTNNA3 in autism comes from two studies. In one genome-wide association study, an imputed SNP in the gene was found to be suggestive of association (Wang et al., 2009). In another study, a TDT analysis showed positive association in 318 trios but was not replicated in a second cohort (Weiss et al., 2009).

Reports Added
[Genetic association of CTNNA3 with late-onset Alzheimer's disease in females.2007] [Common genetic variants on 5p14.1 associate with autism spectrum disorders.2009] [A genome-wide linkage and association scan reveals novel loci for autism.2009] [Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.2013] [Identification of risk genes for autism spectrum disorder through copy number variation analysis in Austrian families.2014] [A CTNNA3 compound heterozygous deletion implicates a role for T-catenin in susceptibility to autism spectrum disorder.2014] [Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene ...2014] [Epileptic encephalopathies of the Landau-Kleffner and continuous spike and waves during slow-wave sleep types: genomic dissection makes the link wi...2012] [Alpha-T-catenin (CTNNA3) gene was identified as a risk variant for toluene diisocyanate-induced asthma by genome-wide association analysis.2009] [The contribution of de novo coding mutations to autism spectrum disorder2014]
7/1/2014
No data
icon
4

Increased from No data to 4

Description

Evidence for the role of CTNNA3 in autism comes from two studies. In one genome-wide association study, an imputed SNP in the gene was found to be suggestive of association (Wang et al., 2009). In another study, a TDT analysis showed positive association in 318 trios but was not replicated in a second cohort (Weiss et al., 2009).

Reports Added
[Genetic association of CTNNA3 with late-onset Alzheimer's disease in females.2007] [Alpha-T-catenin (CTNNA3) gene was identified as a risk variant for toluene diisocyanate-induced asthma by genome-wide association analysis.2009] [Common genetic variants on 5p14.1 associate with autism spectrum disorders.2009] [A genome-wide linkage and association scan reveals novel loci for autism.2009] [Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [Epileptic encephalopathies of the Landau-Kleffner and continuous spike and waves during slow-wave sleep types: genomic dissection makes the link wi...2012] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.2013] [Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene ...2014] [Identification of risk genes for autism spectrum disorder through copy number variation analysis in Austrian families.2014] [A CTNNA3 compound heterozygous deletion implicates a role for T-catenin in susceptibility to autism spectrum disorder.2014]
4/1/2014
No data
icon
4

Increased from No data to 4

Description

Evidence for the role of CTNNA3 in autism comes from two studies. In one genome-wide association study, an imputed SNP in the gene was found to be suggestive of association (Wang et al., 2009). In another study, a TDT analysis showed positive association in 318 trios but was not replicated in a second cohort (Weiss et al., 2009).

Reports Added
[Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene ...2014] [Identification of risk genes for autism spectrum disorder through copy number variation analysis in Austrian families.2014]
Krishnan Probability Score

Score 0.49904454687045

Ranking 2194/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 6.5425720044068E-8

Ranking 15780/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.51358667758901

Ranking 478/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Larsen Cumulative Evidence Score

Score 35

Ranking 61/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score -0.05323245310532

Ranking 10518/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
External PIN Data
BioGRIDHuman Protein Reference Database
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
CDH12 Cadherin-12 Human Protein Binding 1010 P55289
CDH24 cadherin 24, type 2 Human Protein Binding 64403 Q86UP0
CDH4 cadherin 4, type 1, R-cadherin (retinal) Human Protein Binding 1002 P55283
FAM123B APC membrane recruitment protein 1 Human Protein Binding 139285 Q5JTC6
gag Gag polyprotein HIV-1 Protein Binding 155030 Q9IDV8
OSBPL1A oxysterol binding protein-like 1A Human Protein Binding 114876 Q9BXW6
PRKAA2 protein kinase, AMP-activated, alpha 2 catalytic subunit Human Protein Binding 5563 P54646
RELL1 RELT-like protein 1 Human Protein Binding 768211 Q8IUW5
VMA21 VMA21 vacuolar H+-ATPase homolog (S. cerevisiae) Human Protein Binding 203547 Q3ZAQ7
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