Human Gene Module / Chromosome 6 / RIMS1

RIMS1Regulating synaptic membrane exocytosis 1

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
3 / 5
Rare Variants / Common Variants
9 / 1
Aliases
RIMS1, RP5-1046G13.1,  CORD7,  RAB3IP2,  RIM,  RIM1
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Genetic Association
Chromosome Band
6q13
Associated Disorders
-
Relevance to Autism

De novo frameshift variants in this gene have been identified in unrelated ASD cases from the Simons Simplex Collection (Iossifov et al., 2012; Dong et al., 2014).

Molecular Function

Rab effector involved in exocytosis. May act as scaffold protein that regulates neurotransmitter release at the active zone. Essential for maintaining normal probability of neurotransmitter release and for regulating release during short-term synaptic plasticity. Mutations in this gene have suggested to play a role in cognition and have been identified as the cause of cone-rod dystrophy type 7 (CORD7) [MIM:603649].

Reports related to RIMS1 (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support De novo gene disruptions in children on the autistic spectrum. Iossifov I , et al. (2012) Yes -
2 Primary De novo insertions and deletions of predominantly paternal origin are associated with autism spectrum disorder. Dong S , et al. (2014) Yes -
3 Support De novo genic mutations among a Chinese autism spectrum disorder cohort. Wang T , et al. (2016) Yes -
4 Positive Association Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Pardias AF , et al. (2018) No -
5 Recent Recommendation Postsynaptic RIM1 modulates synaptic function by facilitating membrane delivery of recycling NMDARs in hippocampal neurons. Wang J , et al. (2018) No -
Rare Variants   (9)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.586dupA p.Asp195fs frameshift_variant De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.174_175insA p.Arg58fs frameshift_variant De novo - Simplex 25284784 Dong S , et al. (2014)
c.3264C>A p.Cys1088Ter stop_gained De novo - - 27824329 Wang T , et al. (2016)
c.3139del p.Thr1047HisfsTer31 frameshift_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.3139del p.Thr1047HisfsTer31 frameshift_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.4045G>T p.Ala1349Ser missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.981C>G p.Tyr327Ter stop_gained Familial Maternal - 27824329 Wang T , et al. (2016)
c.3430C>T p.Arg1144Ter stop_gained Familial Paternal - 27824329 Wang T , et al. (2016)
c.3522_3523del p.Gln1174HisfsTer2 frameshift_variant Unknown Not maternal - 27824329 Wang T , et al. (2016)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
C>T - intergenic_variant - - - 29483656 Pardias AF , et al. (2018)
SFARI Gene score
2

Strong Candidate

2

Score Delta: Score remained at 2.1

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.

10/1/2016
3
icon
2

Decreased from 3 to 2

Description

De novo loss-of-function frameshift variants in the RIMS1 gene have been identified in two unrelated ASD cases from the Simons Simplex Collection (PMIDs 22542183, 25284784); no similar indels were observed in controls. A third de novo LoF variant in NCKAP1 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016.

10/1/2014
icon
3

Increased from to 3

Description

De novo loss-of-function frameshift variants in the RIMS1 gene have been identified in two unrelated ASD cases from the Simons Simplex Collection (PMIDs 22542183, 25284784); no similar indels were observed in controls.

Krishnan Probability Score

Score 0.5778281004324

Ranking 622/25841 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 0.029211449434764

Ranking 9068/18225 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 0.17353078261678

Ranking 97/18665 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 22

Ranking 95/461 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 0.4699594120341

Ranking 748/20870 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.
CNVs associated with RIMS1(1 CNVs)
6q13 9 Deletion 17  /  29
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
RAB26 Ras-related protein Rab-26 Mouse Protein Binding 328778 Q504M8
RAB37 Ras-related protein Rab-37 Mouse Protein Binding 58222 Q9JKM7
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