Human Gene Module / Chromosome 2 / ADCY3

ADCY3adenylate cyclase 3

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 4
Rare Variants / Common Variants
7 / 0
Aliases
ADCY3, AC-III,  AC3
Associated Syndromes
-
Chromosome Band
2p23.3
Associated Disorders
-
Relevance to Autism

Three de novo missense variants in the ADCY3 gene were identified in ASD probands from the Autism Sequencing Consortium in De Rubeis et al., 2014. A fourth de novo missense variant in this gene was identified by whole genome sequencing in an ASD proband as part of the MSSNG initiative in Yuen et al., 2017. Based on the discovery of four de novo missense variants in ASD cases, a z-score > 2.0 for missense mutations, and a higher-than expected mutation rate (a false discovery rate < 15%), ADCY3 was determined to be an ASD candidate gene in Yuen et al., 2017.

Molecular Function

This gene encodes adenylyl cyclase 3 which is a membrane-associated enzyme and catalyzes the formation of the secondary messenger cyclic adenosine monophosphate (cAMP).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ADCY3 (4 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Recent Recommendation Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
3 Support - Zhou X et al. (2022) Yes -
4 Support - Cirnigliaro M et al. (2023) Yes -
Rare Variants   (7)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2737G>A p.Glu913Lys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.933C>T p.Tyr311%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.1481C>T p.Ala494Val missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.1729G>A p.Val577Met missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.3356T>C p.Phe1119Ser missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.2843G>A p.Cys948Tyr missense_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.1318del p.Thr440LeufsTer2 frameshift_variant Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Three de novo missense variants in the ADCY3 gene were identified in ASD probands from the Autism Sequencing Consortium in De Rubeis et al., 2014. A fourth de novo missense variant in this gene was identified by whole genome sequencing in an ASD proband as part of the MSSNG initiative in Yuen et al., 2017. Based on the discovery of four de novo missense variants in ASD cases, a z-score > 2.0 for missense mutations, and a higher-than expected mutation rate (a false discovery rate < 15%), ADCY3 was determined to be an ASD candidate gene in Yuen et al., 2017.

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.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

Three de novo missense variants in the ADCY3 gene were identified in ASD probands from the Autism Sequencing Consortium in De Rubeis et al., 2014. A fourth de novo missense variant in this gene was identified by whole genome sequencing in an ASD proband as part of the MSSNG initiative in Yuen et al., 2017. Based on the discovery of four de novo missense variants in ASD cases, a z-score > 2.0 for missense mutations, and a higher-than expected mutation rate (a false discovery rate < 15%), ADCY3 was determined to be an ASD candidate gene in Yuen et al., 2017.

Reports Added
[New Scoring Scheme]
4/1/2017
icon
3

Increased from to 3

Description

Three de novo missense variants in the ADCY3 gene were identified in ASD probands from the Autism Sequencing Consortium in De Rubeis et al., 2014. A fourth de novo missense variant in this gene was identified by whole genome sequencing in an ASD proband as part of the MSSNG initiative in Yuen et al., 2017. Based on the discovery of four de novo missense variants in ASD cases, a z-score > 2.0 for missense mutations, and a higher-than expected mutation rate (a false discovery rate < 15%), ADCY3 was determined to be an ASD candidate gene in Yuen et al., 2017.

Krishnan Probability Score

Score 0.49229440146818

Ranking 4618/25841 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 0.0013793010146909

Ranking 11558/18225 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 0.70933840984798

Ranking 1218/18665 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
Zhang D Score

Score 0.18747801114765

Ranking 4471/20870 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
Submit New Gene

Report an Error