Human Gene Module / Chromosome 2 / RAPGEF4

RAPGEF4Rap guanine nucleotide exchange factor (GEF) 4

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
7 / 17
Rare Variants / Common Variants
9 / 0
Aliases
RAPGEF4, CGEF2,  EPAC2,  Nbla00496,  CAMP-GEFII
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation
Chromosome Band
2q31.1
Associated 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.

Reports related to RAPGEF4 (17 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 s... 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 Highly Cited A family of cAMP-binding proteins that directly activate Rap1. Kawasaki H , et al. (1998) No -
Rare Variants   (9)
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 NA - 25363760 De Rubeis S , et al. (2014)
c.105C>T p.Asn35%3D synonymous_variant De novo NA - 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 NA Multiplex 31398340 Ruzzo EK , et al. (2019)
c.2210A>G p.Asn737Ser missense_variant De novo NA Simplex 25363768 Iossifov I , et al. (2014)
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
3

Suggestive Evidence

A single, unreplicated association of nonsynonymous variants has been reported by Bacchelli et al., 2003 (PMID: 14593429).

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

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
icon
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
icon
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
icon
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
icon
4

Decreased from 4 to 4

Description

A single, unreplicated association of nonsynonymous variants has been reported by Bacchelli et al., 2003 (PMID: 14593429).

7/1/2014
No data
icon
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
icon
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 Washington’s 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.
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
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We are pleased to announce some changes to the ongoing curation of the data in SFARI Gene. In the context of a continued effort to develop the human gene module and its manually curated list of autism risk genes, we are modifying other aspects of the site to focus on the information that is of greatest interest to the research community. The version of SFARI Gene that has been developed until now will be frozen and will remain available as “SFARI Gene Archive”. Please see the announcement for more details.
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