Human Gene Module / Chromosome 1 / ADORA3

ADORA3Adenosine A3 receptor

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
1 / 2
Rare Variants / Common Variants
5 / 0
Aliases
ADORA3, RP11-552M11.7,  A3AR,  AD026,  bA552M11.5
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Functional
Chromosome Band
1p13.2
Associated Disorders
-
Relevance to Autism

Sequencing of the ADORA3 gene in a case-control sample showed an overall increase in rare coding variants in ASD cases vs. controls (P=0.013); among the case-specific ADORA3 coding variants were two rare missense variants (Leu90Val and Val171Ile) that affected activity of SERT, the gene product of the ASD-associated gene SLC6A4 (Campbell et al., 2013).

Molecular Function

This gene encodes a protein that belongs to the family of adenosine receptors, which are G-protein-coupled receptors that are involved in a variety of intracellular signaling pathways and physiological functions. The receptor encoded by this gene mediates a sustained cardioprotective function during cardiac ischemia, it is involved in the inhibition of neutrophil degranulation in neutrophil-mediated tissue injury, it has been implicated in both neuroprotective and neurodegenerative effects, and it may also mediate both cell proliferation and cell death.

Reports related to ADORA3 (2 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Colocalization and regulated physical association of presynaptic serotonin transporters with A adenosine receptors. Zhu CB , et al. (2011) No -
2 Primary Rare coding variants of the adenosine A3 receptor are increased in autism: on the trail of the serotonin transporter regulome. Campbell NG , et al. (2013) Yes -
Rare Variants   (5)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.511G>A p.Val171Ile missense_variant De novo NA Simplex 23953133 Campbell NG , et al. (2013)
c.268C>G p.Leu90Val missense_variant Familial Paternal Multiplex 23953133 Campbell NG , et al. (2013)
c.511G>A p.Val171Ile missense_variant Familial Maternal Multiplex 23953133 Campbell NG , et al. (2013)
c.511G>A p.Val171Ile missense_variant Familial Paternal Multiplex 23953133 Campbell NG , et al. (2013)
c.268C>G p.Leu90Val missense_variant Familial (n=3) Maternal Multiplex 23953133 Campbell NG , et al. (2013)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

Sequencing of the ADORA3 gene in a case-control sample showed an overall increase in rare coding variants in ASD cases vs. controls (P=0.013); among the case-specific ADORA3 coding variants were two rare missense variants (p.Leu90Val and p.Val171Ile) that affected activity of SERT, the gene product of the ASD-associated gene SLC6A4 (Campbell et al., 2013).

Score Delta: Decreased from 4 to 3

3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Sequencing of the ADORA3 gene in a case-control sample showed an overall increase in rare coding variants in ASD cases vs. controls (P=0.013); among the case-specific ADORA3 coding variants were two rare missense variants (p.Leu90Val and p.Val171Ile) that affected activity of SERT, the gene product of the ASD-associated gene SLC6A4 (Campbell et al., 2013).

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

Increased from to 4

Description

Sequencing of the ADORA3 gene in a case-control sample showed an overall increase in rare coding variants in ASD cases vs. controls (P=0.013); among the case-specific ADORA3 coding variants were two rare missense variants (p.Leu90Val and p.Val171Ile) that affected activity of SERT, the gene product of the ASD-associated gene SLC6A4 (Campbell et al., 2013).

Krishnan Probability Score

Score 0.49211164445913

Ranking 4733/25841 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.
ExAC Score

Score 0.006057306455452

Ranking 10414/18225 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
Sanders TADA Score

Score 0.93369409027253

Ranking 12345/18665 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).
Larsen Cumulative Evidence Score

Score 34

Ranking 63/461 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.
Zhang D Score

Score 0.016230128878669

Ranking 8191/20870 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.
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SFARI Gene Update

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