Human Gene Module / Chromosome 19 / CNOT3

CNOT3CCR4-NOT transcription complex subunit 3

Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
4 / 5
Rare Variants / Common Variants
8 / 0
Aliases
CNOT3, LENG2,  NOT3,  NOT3H
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
19q13.42
Associated Disorders
ASD
Relevance to Autism

Analysis of de novo variants identified in patients from the Deciphering Developmental Disorders (DDD) Study cohort, along with meta-analysis of probands from previously published studies, identified CNOT3 as a gene exceeding genome-wide significance (P<7.0E-07) (Deciphering Developmental Disorders Study, 2017). Of the seven cases with de novo variants in the CNOT3 gene from the DDD cohort, four (DECIPHER IDs 257816, 259521, 262450, and 263217) were reported to have the Human Phenotype Ontology (HPO) term "Autism spectrum disorder". A de novo frameshift variant in CNOT3 had previously been observed in an ASD proband from the Simons Simplex Collection (O'Roak et al., 2012).

Molecular Function

This gene encodes for a component of the CCR4-NOT complex which is one of the major cellular mRNA deadenylases and is linked to various cellular processes including bulk mRNA degradation, miRNA-mediated repression, translational repression during translational initiation and general transcription regulation.

Reports related to CNOT3 (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. O'Roak BJ , et al. (2012) Yes -
2 Support Recurrent de novo mutations implicate novel genes underlying simplex autism risk. O'Roak BJ , et al. (2014) Yes -
3 Primary Prevalence and architecture of de novo mutations in developmental disorders. Deciphering Developmental Disorders Study (2017) No ASD
4 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. C Yuen RK , et al. (2017) Yes -
5 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model. Guo H , et al. (2018) Yes -
Rare Variants   (8)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
delTG - frameshift_variant De novo - Simplex 22495309 O'Roak BJ , et al. (2012)
- - missense_variant De novo - - 28135719 Deciphering Developmental Disorders Study (2017)
- - frameshift_variant De novo - - 28135719 Deciphering Developmental Disorders Study (2017)
c.634G>A p.Asp212Asn missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.1473_1474del p.Ser491fs frameshift_variant De novo - Simplex 28263302 C Yuen RK , et al. (2017)
c.2080C>T p.Gln694Ter stop_gained De novo - - 28135719 Deciphering Developmental Disorders Study (2017)
c.724_725insC p.Pro244SerfsTer9 frameshift_variant De novo - Simplex 25418537 O'Roak BJ , et al. (2014)
c.563G>A p.Arg188His missense_variant De novo - - 28135719 Deciphering Developmental Disorders Study (2017)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

3S

Score Delta: Score remained at 3.3 + S

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.

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2017
4S
icon
3S

Decreased from 4S to 3S

Description

Analysis of de novo variants identified in patients from the Deciphering Developmental Disorders (DDD) Study cohort, along with meta-analysis of probands from previously published studies, identified CNOT3 as a gene exceeding genome-wide significance (P<7.0E-07) (Deciphering Developmental Disorders Study, 2017). Of the seven cases with de novo variants in the CNOT3 gene from the DDD cohort, four (DECIPHER IDs 257816, 259521, 262450, and 263217) were reported to have the Human Phenotype Ontology (HPO) term "Autism spectrum disorder". Other recurrent HPO terms used in cases with CNOT3 variants were abnormal axial skeleton morphology and global developmental delay. A de novo frameshift variant in CNOT3 had previously been observed in an ASD proband from the Simons Simplex Collection (O'Roak et al., 2012). A second de novo frameshift variant in CNOT3 was identified in an ASD proband from a simplex family from the ASD: Genomes to Outcome Study cohort by whole genome sequencing as part of the MSSNG initiative in Yuen et al., 2017. Based on the discovery of two de novo LoF variants in this gene in ASD probands, a probability of LoF intolerance rate (pLI) > 0.9, and higher-than-expected mutation rate (false discovery rate < 15%), CNOT3 was classified as an ASD candidate gene in Yuen et al., 2017.

1/1/2017
icon
4S

Increased from to 4S

Description

Analysis of de novo variants identified in patients from the Deciphering Developmental Disorders (DDD) Study cohort, along with meta-analysis of probands from previously published studies, identified CNOT3 as a gene exceeding genome-wide significance (P<7.0E-07) (Deciphering Developmental Disorders Study, 2017). Of the seven cases with de novo variants in the CNOT3 gene from the DDD cohort, four (DECIPHER IDs 257816, 259521, 262450, and 263217) were reported to have the Human Phenotype Ontology (HPO) term "Autism spectrum disorder". Other recurrent HPO terms used in cases with CNOT3 variants were abnormal axial skeleton morphology and global developmental delay. A de novo frameshift variant in CNOT3 had previously been observed in an ASD proband from the Simons Simplex Collection (O'Roak et al., 2012).

Krishnan Probability Score

Score 0.5108559432075

Ranking 1829/25841 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 0.99996722242186

Ranking 552/18225 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 0.951

Ranking 81/239 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 0.5267533821057

Ranking 508/18665 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).
Zhang D Score

Score 0.31714577786151

Ranking 2482/20870 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 CNOT3(1 CNVs)
19q13.42 28 Deletion-Duplication 46  /  127
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