Human Gene Module / Chromosome 1 / AGO1

AGO1argonaute 1, RISC catalytic component

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
7 / 15
Rare Variants / Common Variants
34 / 0
Aliases
AGO1, EIF2C,  EIF2C1,  GERP95,  Q99,  hAgo1
Associated Syndromes
-
Chromosome Band
1p34.3
Associated Disorders
EP, EPS
Relevance to Autism

De novo missense variants that were predicted in silico to be damaging were observed in the AGO1 gene in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014) and an ASD proband from a cohort of 262 Japanese trios (Takata et al., 2018). TADA-Denovo analysis using a combined dataset of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium, as well as the Japanese ASD cohort from Takata et al., 2018, identified AGO1 as a gene significantly enriched in damaging de novo mutations in ASD cases (pBH < 0.05).

Molecular Function

This gene encodes a member of the argonaute family of proteins, which associate with small RNAs and have important roles in RNA interference (RNAi) and RNA silencing. This protein binds to microRNAs (miRNAs) or small interfering RNAs (siRNAs) and represses translation of mRNAs that are complementary to them. It is also involved in transcriptional gene silencing (TGS) of promoter regions that are complementary to bound short antigene RNAs (agRNAs), as well as in the degradation of miRNA-bound mRNA targets.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to AGO1 (15 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study Rauch A , et al. (2012) No Absent speech,motor delay
2 Support De novo mutations in moderate or severe intellectual disability Hamdan FF , et al. (2014) No Speech delay
3 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
4 Support High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing Martnez F , et al. (2016) No Speech delay, motor delay
5 Recent Recommendation Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder Takata A , et al. (2018) Yes -
6 Recent recommendation Further evidence of a causal association between AGO1, a critical regulator of microRNA formation, and intellectual disability/autism spectrum disorder Sakaguchi A , et al. (2018) No Epilepsy/seizures
7 Support Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort Callaghan DB , et al. (2019) Yes -
8 Recent Recommendation - Schalk A et al. (2021) No ASD or autistic behavior, stereotypy, epilepsy/sei
9 Recent Recommendation - Niu Y et al. (2022) No -
10 Support - Zhou X et al. (2022) Yes -
11 Support - Spataro N et al. (2023) No Autistic features
12 Support - Hu C et al. (2023) Yes -
13 Support - Kipkemoi P et al. (2023) No Stereotypy
14 Support - Mir A et al. (2023) Yes Epilepsy/seizures
15 Recent Recommendation - et al. () Yes -
Rare Variants   (34)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.650-2A>G - splice_site_variant De novo - - 34930816 Schalk A et al. (2021)
c.370C>G p.Arg124Gly missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.758G>A p.Arg253His missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1492A>G p.Ser498Gly missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.569T>C p.Leu190Pro missense_variant De novo - - 23020937 Rauch A , et al. (2012)
c.566C>T p.Pro189Leu missense_variant De novo - - 34930816 Schalk A et al. (2021)
c.569T>G p.Leu190Arg missense_variant De novo - - 34930816 Schalk A et al. (2021)
c.595G>A p.Gly199Ser missense_variant De novo - - 34930816 Schalk A et al. (2021)
c.758G>A p.Arg253His missense_variant De novo - - 34930816 Schalk A et al. (2021)
c.760G>A p.Val254Ile missense_variant De novo - - 34930816 Schalk A et al. (2021)
c.971C>T p.Pro324Leu missense_variant De novo - - 34930816 Schalk A et al. (2021)
c.512+8G>A - splice_region_variant Familial Paternal - 37007974 Hu C et al. (2023)
c.1073A>G p.Gln358Arg missense_variant De novo - - 34930816 Schalk A et al. (2021)
c.2389A>T p.Ile797Phe missense_variant De novo - - 34930816 Schalk A et al. (2021)
c.539_541del p.Phe180del inframe_deletion De novo - - 35982159 Zhou X et al. (2022)
c.595G>A p.Gly199Ser missense_variant De novo - - 25356899 Hamdan FF , et al. (2014)
c.583G>A p.Glu195Lys missense_variant De novo - - 27620904 Martnez F , et al. (2016)
c.595G>A p.Gly199Ser missense_variant De novo - Simplex 35060114 Niu Y et al. (2022)
c.539_541del p.Phe180del inframe_deletion De novo - - 34930816 Schalk A et al. (2021)
c.583G>A p.Glu195Lys missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.539_541del p.Phe180del inframe_deletion De novo - - 36980980 Spataro N et al. (2023)
c.1126_1128del p.Glu376del inframe_deletion De novo - - 34930816 Schalk A et al. (2021)
c.539_541del p.Phe180del inframe_deletion De novo - Simplex 35060114 Niu Y et al. (2022)
c.1253A>T p.Tyr418Phe missense_variant Unknown - Unknown 34930816 Schalk A et al. (2021)
c.596G>T p.Gly199Val missense_variant De novo - Simplex 29346770 Takata A , et al. (2018)
c.1298G>A p.Trp433Ter stop_gained Familial Paternal Simplex 37589173 Mir A et al. (2023)
c.971C>T p.Pro324Leu missense_variant De novo - Simplex 37463579 Kipkemoi P et al. (2023)
c.1126_1128del p.Glu376del inframe_deletion De novo - Simplex 35060114 Niu Y et al. (2022)
c.2342C>T p.Thr781Met missense_variant Unknown - Multiplex 34930816 Schalk A et al. (2021)
c.1064C>T p.Thr355Ile missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.595G>A p.Gly199Ser missense_variant De novo - Simplex 30213762 Sakaguchi A , et al. (2018)
c.2399C>T p.Pro800Leu missense_variant Unknown - Simplex 31038196 Callaghan DB , et al. (2019)
c.569T>C p.Leu190Pro missense_variant De novo - Multiplex (monozygotic twins) 34930816 Schalk A et al. (2021)
c.2252A>T p.His751Leu missense_variant De novo - Multiplex (monozygotic twins) 34930816 Schalk A et al. (2021)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

De novo missense variants that were predicted in silico to be damaging were observed in the AGO1 gene in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014) and an ASD proband from a cohort of 262 Japanese trios (Takata et al., 2018). TADA-Denovo analysis using a combined dataset of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium, as well as the Japanese ASD cohort from Takata et al., 2018, identified AGO1 as a gene significantly enriched in damaging de novo mutations in ASD cases (pBH < 0.05). De novo missense variants in the AGO1 gene that were predicted in silico to be damaging have also been identified in individuals presenting with intellectual disability; epilepsy, speech delay, and/or autistic behavior and stereotypic behavior have been observed in a subset of these individuals (Rauch et al., 2012; Hamdan et al., 2014; Martinez et al., 2017; Sakaguchi et al., 2018).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
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.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

De novo missense variants that were predicted in silico to be damaging were observed in the AGO1 gene in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014) and an ASD proband from a cohort of 262 Japanese trios (Takata et al., 2018). TADA-Denovo analysis using a combined dataset of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium, as well as the Japanese ASD cohort from Takata et al., 2018, identified AGO1 as a gene significantly enriched in damaging de novo mutations in ASD cases (pBH < 0.05). De novo missense variants in the AGO1 gene that were predicted in silico to be damaging have also been identified in individuals presenting with intellectual disability; epilepsy, speech delay, and/or autistic behavior and stereotypic behavior have been observed in a subset of these individuals (Rauch et al., 2012; Hamdan et al., 2014; Martinez et al., 2017; Sakaguchi et al., 2018).

Reports Added
[New Scoring Scheme]
4/1/2019
3
icon
3

Decreased from 3 to 3

Description

De novo missense variants that were predicted in silico to be damaging were observed in the AGO1 gene in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014) and an ASD proband from a cohort of 262 Japanese trios (Takata et al., 2018). TADA-Denovo analysis using a combined dataset of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium, as well as the Japanese ASD cohort from Takata et al., 2018, identified AGO1 as a gene significantly enriched in damaging de novo mutations in ASD cases (pBH < 0.05). De novo missense variants in the AGO1 gene that were predicted in silico to be damaging have also been identified in individuals presenting with intellectual disability; epilepsy, speech delay, and/or autistic behavior and stereotypic behavior have been observed in a subset of these individuals (Rauch et al., 2012; Hamdan et al., 2014; Martinez et al., 2017; Sakaguchi et al., 2018).

Reports Added
[Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort.2019]
10/1/2018
4
icon
3

Decreased from 4 to 3

Description

De novo missense variants that were predicted in silico to be damaging were observed in the AGO1 gene in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014) and an ASD proband from a cohort of 262 Japanese trios (Takata et al., 2018). TADA-Denovo analysis using a combined dataset of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium, as well as the Japanese ASD cohort from Takata et al., 2018, identified AGO1 as a gene significantly enriched in damaging de novo mutations in ASD cases (pBH < 0.05). De novo missense variants in the AGO1 gene that were predicted in silico to be damaging have also been identified in individuals presenting with intellectual disability; epilepsy, speech delay, and/or autistic behavior and stereotypic behavior have been observed in a subset of these individuals (Rauch et al., 2012; Hamdan et al., 2014; Martinez et al., 2017; Sakaguchi et al., 2018).

Reports Added
[Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.2012] [De novo mutations in moderate or severe intellectual disability.2014] [High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing.2016] [Further evidence of a causal association between AGO1, a critical regulator of microRNA formation, and intellectual disability/autism spectrum diso...2018]
7/1/2018
icon
4

Increased from to 4

Description

De novo missense variants that were predicted in silico to be damaging were observed in the AGO1 gene in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014) and an ASD proband from a cohort of 262 Japanese trios (Takata et al., 2018). TADA-Denovo analysis using a combined dataset of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium, as well as the Japanese ASD cohort from Takata et al., 2018, identified AGO1 as a gene significantly enriched in damaging de novo mutations in ASD cases (pBH < 0.05).

Krishnan Probability Score

Score 0.49238830169244

Ranking 4561/25841 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 0.99999946347142

Ranking 268/18225 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 0.64014937032946

Ranking 855/18665 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
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