Human Gene Module / Chromosome 3 / ADCY5

ADCY5Adenylate cyclase 5

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
8 / 13
Rare Variants / Common Variants
19 / 0
Aliases
ADCY5, AC5,  FDFM
Associated Syndromes
-
Chromosome Band
3q21.1
Associated Disorders
-
Relevance to Autism

De novo variants in this gene were identified in two separate reports using ASD probands from the Simons Simplex Collection (Sanders et al. 2012a, 2012b)

Molecular Function

This gene encodes a member of the membrane-bound adenylyl cyclase enzymes. Adenylyl cyclases mediate G protein-coupled receptor signaling through the synthesis of the second messenger cAMP. Activity of the encoded protein is stimulated by the Gs alpha subunit of G protein-coupled receptors and is inhibited by protein kinase A, calcium and Gi alpha subunits.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ADCY5 (13 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations O'Roak BJ , et al. (2012) Yes -
2 Support Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders O'Roak BJ , et al. (2012) Yes -
3 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
4 Support De novo genic mutations among a Chinese autism spectrum disorder cohort Wang T , et al. (2016) Yes -
5 Support A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology Vissers LE , et al. (2017) No Ataxia, chorea, dystonia, tremor
6 Support Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders Li J , et al. (2017) Yes -
7 Support - Brunet T et al. (2021) No -
8 Support - Woodbury-Smith M et al. (2022) Yes -
9 Support - Zhou X et al. (2022) Yes -
10 Support - Tuncay IO et al. (2023) Yes -
11 Support - Noor Smal et al. () No -
12 Support - Axel Schmidt et al. (2024) No -
13 Support - Il Bin Kim et al. (2024) Yes -
Rare Variants   (19)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1582G>A p.Glu528Lys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2026G>A p.Ala676Thr missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2101C>T p.Pro701Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2450A>T p.Glu817Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
- - 2KB_upstream_variant Familial Both parents - 37492102 Tuncay IO et al. (2023)
c.308G>A p.Trp103Ter stop_gained De novo - Simplex 35982159 Zhou X et al. (2022)
c.2101G>A p.His701Tyr missense_variant De novo - - 39085355 Il Bin Kim et al. (2024)
c.2090G>T p.Gly697Val missense_variant De novo - - 28333917 Vissers LE , et al. (2017)
c.1253G>A p.Arg418Gln missense_variant De novo - Simplex 38965372 Noor Smal et al. ()
c.2176G>A p.Ala726Thr missense_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.1717G>A p.Gly573Ser missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.1322C>T p.Ala441Val missense_variant De novo - Simplex 33619735 Brunet T et al. (2021)
c.2071A>G p.Lys691Glu missense_variant De novo - Simplex 33619735 Brunet T et al. (2021)
c.2371G>A p.Asp1141Asn missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.1807C>T p.Arg603Cys missense_variant De novo - Simplex 22495309 O'Roak BJ , et al. (2012)
c.1600G>A p.Ala534Thr missense_variant De novo - Simplex 23160955 O'Roak BJ , et al. (2012)
c.607C>T p.Leu203%3D synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
del(T) p.Gln321ArgfsTer56 frameshift_variant Familial Paternal Simplex 23160955 O'Roak BJ , et al. (2012)
c.2667C>T p.Gly889= synonymous_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Two de novo missense variants and an inherited frameshift variant that was not transmitted to an unaffected sibling were identified in the ADCY5 gene in ASD probands from the Simons Simplex Collection (PMIDs 22495309, 23160955).

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

Two de novo missense variants and an inherited frameshift variant that was not transmitted to an unaffected sibling were identified in the ADCY5 gene in ASD probands from the Simons Simplex Collection (PMIDs 22495309, 23160955).

1/1/2021
3
icon
3

Decreased from 3 to 3

Description

Two de novo missense variants and an inherited frameshift variant that was not transmitted to an unaffected sibling were identified in the ADCY5 gene in ASD probands from the Simons Simplex Collection (PMIDs 22495309, 23160955).

Reports Added
[De novo variants in neurodevelopmental disorders-experiences from a tertiary care center2021]
10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Two de novo missense variants and an inherited frameshift variant that was not transmitted to an unaffected sibling were identified in the ADCY5 gene in ASD probands from the Simons Simplex Collection (PMIDs 22495309, 23160955).

Reports Added
[New Scoring Scheme]
10/1/2017
4
icon
4

Decreased from 4 to 4

Description

Two de novo missense variants and an inherited frameshift variant that was not transmitted to an unaffected sibling were identified in the ADCY5 gene in ASD probands from the Simons Simplex Collection (PMIDs 22495309, 23160955).

Reports Added
[Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders.2017]
4/1/2017
4
icon
4

Decreased from 4 to 4

Description

Two de novo missense variants and an inherited frameshift variant that was not transmitted to an unaffected sibling were identified in the ADCY5 gene in ASD probands from the Simons Simplex Collection (PMIDs 22495309, 23160955).

Reports Added
[Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.2012] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology.2017]
10/1/2016
4
icon
4

Decreased from 4 to 4

Description

Two de novo missense variants and an inherited frameshift variant that was not transmitted to an unaffected sibling were identified in the ADCY5 gene in ASD probands from the Simons Simplex Collection (PMIDs 22495309, 23160955).

Reports Added
[De novo genic mutations among a Chinese autism spectrum disorder cohort.2016]
7/1/2015
icon
4

Increased from to 4

Description

Two de novo missense variants and an inherited frameshift variant that was not transmitted to an unaffected sibling were identified in the ADCY5 gene in ASD probands from the Simons Simplex Collection (PMIDs 22495309, 23160955).

Krishnan Probability Score

Score 0.49293225235494

Ranking 4352/25841 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 0.98994059183761

Ranking 1807/18225 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 0.48040921638764

Ranking 408/18665 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 12

Ranking 154/461 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 0.23465318549869

Ranking 3694/20870 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
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
CHD8 chromodomain helicase DNA binding protein 8 Human DNA Binding 57680 Q9HCK8
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