RAPGEF4Rap guanine nucleotide exchange factor (GEF) 4
Autism Reports / Total Reports
8 / 18Rare Variants / Common Variants
10 / 0Aliases
RAPGEF4, CGEF2, EPAC2, Nbla00496, CAMP-GEFIIAssociated Syndromes
-Chromosome Band
2q31.1Associated Disorders
-Relevance to Autism
Rare variants in the RAPGEF4 gene have been identified with autism; however, the same study found no genetic association between the RAPGEF4 gene and autism in an IMGSAC cohort (Bacchelli et al., 2003).
Molecular Function
The encoded protein acts as a cAMP sensor and mediates cAMP-dependent, protein k inase A-independent exocytosis.
External Links
SFARI Genomic Platforms
Reports related to RAPGEF4 (18 Reports)
| # | Type | Title | Author, Year | Autism Report | Associated Disorders |
|---|---|---|---|---|---|
| 1 | Primary | Screening of nine candidate genes for autism on chromosome 2q reveals rare nonsynonymous variants in the cAMP-GEFII gene | Bacchelli E , et al. (2003) | Yes | - |
| 2 | Recent Recommendation | Valproate-induced alterations in human theca cell gene expression: clues to the association between valproate use and metabolic side effects | Wood JR , et al. (2004) | No | - |
| 3 | Recent Recommendation | Depolarization and Ca(2+) down regulate CB1 receptors and CB1-mediated signaling in cerebellar granule neurons | Vallano ML , et al. (2006) | No | - |
| 4 | Recent Recommendation | Neuronal AKAP150 coordinates PKA and Epac-mediated PKB/Akt phosphorylation | Nijholt IM , et al. (2008) | No | - |
| 5 | Recent Recommendation | Structure of Epac2 in complex with a cyclic AMP analogue and RAP1B | Rehmann H , et al. (2008) | No | - |
| 6 | Recent Recommendation | Ras is required for the cyclic AMP-dependent activation of Rap1 via Epac2 | Liu C , et al. (2008) | No | - |
| 7 | Recent Recommendation | Epac2 induces synapse remodeling and depression and its disease-associated forms alter spines | Woolfrey KM , et al. (2009) | No | - |
| 8 | Recent Recommendation | Mechanism of intracellular cAMP sensor Epac2 activation: cAMP-induced conformational changes identified by amide hydrogen/deuterium exchange mass spectrometry (DXMS) | Li S , et al. (2011) | No | - |
| 9 | Recent Recommendation | EPAC null mutation impairs learning and social interactions via aberrant regulation of miR-124 and Zif268 translation | Yang Y , et al. (2012) | No | - |
| 10 | Recent Recommendation | An autism-associated variant of Epac2 reveals a role for Ras/Epac2 signaling in controlling basal dendrite maintenance in mice | Srivastava DP , et al. (2012) | No | - |
| 11 | Support | Synaptic, transcriptional and chromatin genes disrupted in autism | De Rubeis S , et al. (2014) | Yes | - |
| 12 | Support | The contribution of de novo coding mutations to autism spectrum disorder | Iossifov I et al. (2014) | Yes | - |
| 13 | Recent Recommendation | Low load for disruptive mutations in autism genes and their biased transmission | Iossifov I , et al. (2015) | Yes | - |
| 14 | Support | Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder | Lim ET , et al. (2017) | Yes | - |
| 15 | Support | Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort | Callaghan DB , et al. (2019) | Yes | - |
| 16 | Support | Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks | Ruzzo EK , et al. (2019) | Yes | - |
| 17 | Support | - | Cirnigliaro M et al. (2023) | Yes | - |
| 18 | Highly Cited | A family of cAMP-binding proteins that directly activate Rap1 | Kawasaki H , et al. (1998) | No | - |
Rare Variants (10)
| Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Parental Transmission | Family Type | PubMed ID | Author, Year |
|---|---|---|---|---|---|---|---|---|
| c.2268+1G>A | - | splice_site_variant | De novo | - | - | 25363760 | De Rubeis S , et al. (2014) | |
| c.105C>T | p.Asn35= | synonymous_variant | De novo | - | Simplex | 28714951 | Lim ET , et al. (2017) | |
| c.105+1G>A | - | splice_site_variant | Unknown | - | Simplex | 31038196 | Callaghan DB , et al. (2019) | |
| c.554G>A | p.Arg185Lys | missense_variant | De novo | - | Multiplex | 31398340 | Ruzzo EK , et al. (2019) | |
| c.2210A>G | p.Asn737Ser | missense_variant | De novo | - | Simplex | 25363768 | Iossifov I et al. (2014) | |
| c.85+1G>C | - | splice_site_variant | Familial | Paternal | Multiplex | 37506195 | Cirnigliaro M et al. (2023) | |
| c.494T>C | p.Met165Thr | missense_variant | Familial | Paternal | Multiplex | 14593429 | Bacchelli E , et al. (2003) | |
| c.1936G>T | p.Val646Phe | missense_variant | Familial | Maternal | Multiplex | 14593429 | Bacchelli E , et al. (2003) | |
| c.2116G>A | p.Gly706Arg | missense_variant | Familial | Paternal | Multiplex | 14593429 | Bacchelli E , et al. (2003) | |
| c.2426C>G | p.Thr809Ser | missense_variant | Familial | Paternal | Multiplex | 14593429 | Bacchelli E , et al. (2003) |
Common Variants
No common variants reported.
SFARI Gene score
2
Strong Candidate
A single, unreplicated association of nonsynonymous variants has been reported by Bacchelli et al., 2003 (PMID: 14593429).
Score Delta: Score remained at 2
criteria met
See SFARI Gene'scoring criteriaWe 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
2
Decreased from 3 to 2
Description
A single, unreplicated association of nonsynonymous variants has been reported by Bacchelli et al., 2003 (PMID: 14593429).
10/1/2019
4
3
Decreased from 4 to 3
New Scoring Scheme
Description
A single, unreplicated association of nonsynonymous variants has been reported by Bacchelli et al., 2003 (PMID: 14593429).
Reports Added
[New Scoring Scheme]7/1/2019
4
4
Decreased from 4 to 4
Description
A single, unreplicated association of nonsynonymous variants has been reported by Bacchelli et al., 2003 (PMID: 14593429).
4/1/2019
4
4
Decreased from 4 to 4
Description
A single, unreplicated association of nonsynonymous variants has been reported by Bacchelli et al., 2003 (PMID: 14593429).
7/1/2017
4
4
Decreased from 4 to 4
Description
A single, unreplicated association of nonsynonymous variants has been reported by Bacchelli et al., 2003 (PMID: 14593429).
1/1/2016
4
4
Decreased from 4 to 4
Description
A single, unreplicated association of nonsynonymous variants has been reported by Bacchelli et al., 2003 (PMID: 14593429).
Reports Added
[Screening of nine candidate genes for autism on chromosome 2q reveals rare nonsynonymous variants in the cAMP-GEFII gene.2003] [A family of cAMP-binding proteins that directly activate Rap1.1998] [Valproate-induced alterations in human theca cell gene expression: clues to the association between valproate use and metabolic side effects.2004] [Depolarization and Ca(2) down regulate CB1 receptors and CB1-mediated signaling in cerebellar granule neurons.2006] [Neuronal AKAP150 coordinates PKA and Epac-mediated PKB/Akt phosphorylation.2008] [Structure of Epac2 in complex with a cyclic AMP analogue and RAP1B.2008] [Ras is required for the cyclic AMP-dependent activation of Rap1 via Epac2.2008] [Epac2 induces synapse remodeling and depression and its disease-associated forms alter spines.2009] [Mechanism of intracellular cAMP sensor Epac2 activation: cAMP-induced conformational changes identified by amide hydrogen/deuterium exchange mass s...2011] [EPAC null mutation impairs learning and social interactions via aberrant regulation of miR-124 and Zif268 translation.2012] [An autism-associated variant of Epac2 reveals a role for Ras/Epac2 signaling in controlling basal dendrite maintenance in mice.2012] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [The contribution of de novo coding mutations to autism spectrum disorder2014]7/1/2014
No data
4
Increased from No data to 4
Description
A single, unreplicated association of nonsynonymous variants has been reported by Bacchelli et al., 2003 (PMID: 14593429).
4/1/2014
No data
4
Increased from No data to 4
Description
A single, unreplicated association of nonsynonymous variants has been reported by Bacchelli et al., 2003 (PMID: 14593429).
Krishnan Probability Score
Score 0.57687877959573
Ranking 635/25841 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 0.95722584960245
Ranking 2574/18225 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
Iossifov Probability Score
Score 0.84
Ranking 204/239 scored genes
[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists
239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This
probability metric combines the evidence from de novo likely-gene- disrupting and missense
mutations and assesses it against the background mutation rate in unaffected individuals from the
University of Washingtonâs Exome Variant Sequence database (evs.gs.washington.edu/EVS/).
The list of probability scores can be found here:
www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/-
/DCSupplemental/pnas.1516376112.sd02.xlsx
Sanders TADA Score
Score 0.11991593209214
Ranking 73/18665 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 8
Ranking 233/461 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 0.4446593921984
Ranking 974/20870 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.
External PIN Data
Interactome
- Protein Binding
- DNA Binding
- RNA Binding
- Protein Modification
- Direct Regulation
- ASD-Linked Genes
Interaction Table
| Interactor Symbol | Interactor Name | Interactor Organism | Interactor Type | Entrez ID | Uniprot ID |
|---|---|---|---|---|---|
| Abcc8 | ATP-binding cassette, subfamily C (CFTR/MRP), member 8 | Rat | Protein Binding | 25559 | Q09429 |