Human Gene Module / Chromosome 6 / RIMS1

RIMS1Regulating synaptic membrane exocytosis 1

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
9 / 11
Rare Variants / Common Variants
15 / 1
EAGLE Score
11.35
Strong Learn More
Aliases
RIMS1, RP5-1046G13.1,  CORD7,  RAB3IP2,  RIM,  RIM1
Associated Syndromes
-
Chromosome Band
6q13
Associated Disorders
-
Genetic Category
Rare Single Gene Mutation, Genetic Association
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].

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to RIMS1 (11 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 -
6 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
7 Support Phenotype-to-genotype approach reveals head-circumference-associated genes in an autism spectrum disorder cohort Wu H , et al. (2019) Yes Macrocephaly
8 Support Rare genetic susceptibility variants assessment in autism spectrum disorder: detection rate and practical use Husson T , et al. (2020) Yes -
9 Support - Zhou X et al. (2022) Yes -
10 Support - Cirnigliaro M et al. (2023) Yes -
11 Support - Omri Bar et al. (2024) Yes ID
Rare Variants   (15)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.3264C>A p.Cys1088Ter stop_gained De novo - - 27824329 Wang T , et al. (2016)
c.1980T>C p.Asn660%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
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.3577A>G p.Arg1193Gly missense_variant De novo - Simplex 30564305 Guo H , et al. (2018)
c.1536-963del - frameshift_variant Familial Paternal Simplex 31674007 Wu H , et al. (2019)
c.4045G>T p.Ala1349Ser missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.1625+8331C>T - stop_gained Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.175dup p.Arg59LysfsTer16 frameshift_variant De novo - Simplex 25284784 Dong S , et al. (2014)
c.100+1G>A p.? splice_site_variant Familial Maternal Simplex 32094338 Husson T , et al. (2020)
c.2708G>A p.Arg903Gln missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.1715G>T p.Trp572Leu missense_variant Familial Maternal Simplex 38256266 Omri Bar et al. (2024)
c.586dup p.Thr196AsnfsTer8 frameshift_variant De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.3139del p.Thr1047HisfsTer31 frameshift_variant Familial Maternal - 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
1

High Confidence

Score Delta: Score remained at 1

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 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.

1/1/2020
1
icon
1

Score remained at 1

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.

Reports Added
[Rare genetic susceptibility variants assessment in autism spectrum disorder: detection rate and practical use.2020]
10/1/2019
2
icon
1

Decreased from 2 to 1

New Scoring Scheme
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.

Reports Added
[Phenotype-to-genotype approach reveals head-circumference-associated genes in an autism spectrum disorder cohort.2019] [New Scoring Scheme]
1/1/2019
2
icon
2

Decreased from 2 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.

Reports Added
[Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.2018]
7/1/2018
2
icon
2

Decreased from 2 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.

Reports Added
[Postsynaptic RIM1 modulates synaptic function by facilitating membrane delivery of recycling NMDARs in hippocampal neurons.2018]
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.

Reports Added
[De novo genic mutations among a Chinese autism spectrum disorder cohort.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.
Original Source
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
Original Source
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).
Original Source
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.
Original Source
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.
Original Source
Interactome
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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