Human Gene Module / Chromosome 19 / CNOT3

CNOT3CCR4-NOT transcription complex subunit 3

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
4 / 8
Rare Variants / Common Variants
24 / 0
Aliases
CNOT3, LENG2,  NOT3,  NOT3H
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
19q13.42
Associated Disorders
DD/NDD, ID, 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 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 (8 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 et al. (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 -
6 Support De novo variants in CNOT3 cause a variable neurodevelopmental disorder. Martin R , et al. (2019) No ASD
7 Support Increased diagnostic and new genes identification outcome using research reanalysis of singleton exome sequencing. Bruel AL , et al. (2019) No ASD
8 Support Inherited cases of CNOT3-associated intellectual developmental disorder with speech delay, autism, and dysmorphic facies Meyer R et al. (2020) No DD, ID
Rare Variants   (24)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2080C>T p.Gln694Ter stop_gained De novo NA - 28135719 et al. (2017)
c.58G>C p.Glu20Gln missense_variant De novo NA - 28135719 et al. (2017)
c.142C>G p.Leu48Val missense_variant De novo NA - 28135719 et al. (2017)
c.562C>T p.Arg188Cys missense_variant De novo NA - 28135719 et al. (2017)
c.563G>A p.Arg188His missense_variant De novo NA - 28135719 et al. (2017)
c.1866G>A p.Trp622Ter stop_gained De novo NA - 31201375 Martin R , et al. (2019)
c.728dup p.Ser245GlnfsTer8 frameshift_variant De novo NA - 28135719 et al. (2017)
c.355A>G p.Lys119Glu missense_variant De novo NA - 31201375 Martin R , et al. (2019)
c.439G>A p.Glu147Lys missense_variant De novo NA - 31201375 Martin R , et al. (2019)
c.1792G>A p.Gly598Ser missense_variant De novo NA - 31201375 Martin R , et al. (2019)
c.1628_1629del p.Leu543Ter frameshift_variant De novo NA - 31201375 Martin R , et al. (2019)
c.658G>T p.Glu220Ter stop_gained Familial Maternal Multiplex 32720325 Meyer R et al. (2020)
c.52G>A p.Val18Met missense_variant Familial Maternal Simplex 32720325 Meyer R et al. (2020)
c.634G>A p.Asp212Asn missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.523_527dup p.His176GlnfsTer10 frameshift_variant De novo NA - 31201375 Martin R , et al. (2019)
c.1127_1145del p.Ala376GlyfsTer61 frameshift_variant De novo NA - 31201375 Martin R , et al. (2019)
c.1240_1243del p.Ser414ValfsTer28 frameshift_variant De novo NA - 31201375 Martin R , et al. (2019)
c.1473_1474del p.Gly493ThrfsTer21 frameshift_variant De novo NA - 31201375 Martin R , et al. (2019)
c.1127_1145del p.Ala376GlyfsTer61 frameshift_variant De novo NA - 31231135 Bruel AL , et al. (2019)
c.1538_1541del p.Ser513MetfsTer27 frameshift_variant De novo NA - 31231135 Bruel AL , et al. (2019)
c.1926_1927del p.Cys643SerfsTer39 frameshift_variant De novo NA - 31231135 Bruel AL , et al. (2019)
c.728dup p.Ser245GlnfsTer8 frameshift_variant De novo NA Simplex 25418537 O'Roak BJ , et al. (2014)
c.1473_1474del p.Gly493ThrfsTer21 frameshift_variant De novo NA Simplex 28263302 C Yuen RK et al. (2017)
c.1976_1977del p.Thr659SerfsTer23 frameshift_variant De novo NA Simplex 22495309 O'Roak BJ , et al. (2012)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

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. Resequencing of 64 candidate neurodevelopmental disorder risk genes by molecular inversion probes in ORoak et al., 2014 identified a third de novo LoF variant in the CNOT3 gene in an ASD proband from The Autism Simplex Collection (TASC). Detailed phenotypic characterization of the seven previously described individuals with de novo CNOT3 variants from the 2017 Deciphering Developmental Disorders Study report and nine previously unpublished individuals with de novo CNOT3 variants in Martin et al., 2019 found that eight individuals presented with either autism, autism spectrum disorder, or PDD-NOS.

Score Delta: Score remained at 2S

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.

7/1/2020
2S
icon
2S

Score remained at 2S

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. Resequencing of 64 candidate neurodevelopmental disorder risk genes by molecular inversion probes in ORoak et al., 2014 identified a third de novo LoF variant in the CNOT3 gene in an ASD proband from The Autism Simplex Collection (TASC). Detailed phenotypic characterization of the seven previously described individuals with de novo CNOT3 variants from the 2017 Deciphering Developmental Disorders Study report and nine previously unpublished individuals with de novo CNOT3 variants in Martin et al., 2019 found that eight individuals presented with either autism, autism spectrum disorder, or PDD-NOS.

10/1/2019
2S
icon
1

Decreased from 2S to 1

New Scoring Scheme
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. Resequencing of 64 candidate neurodevelopmental disorder risk genes by molecular inversion probes in ORoak et al., 2014 identified a third de novo LoF variant in the CNOT3 gene in an ASD proband from The Autism Simplex Collection (TASC). Detailed phenotypic characterization of the seven previously described individuals with de novo CNOT3 variants from the 2017 Deciphering Developmental Disorders Study report and nine previously unpublished individuals with de novo CNOT3 variants in Martin et al., 2019 found that eight individuals presented with either autism, autism spectrum disorder, or PDD-NOS.

Reports Added
[New Scoring Scheme]
7/1/2019
2S
icon
2S

Decreased from 2S to 2S

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. Resequencing of 64 candidate neurodevelopmental disorder risk genes by molecular inversion probes in ORoak et al., 2014 identified a third de novo LoF variant in the CNOT3 gene in an ASD proband from The Autism Simplex Collection (TASC). Detailed phenotypic characterization of the seven previously described individuals with de novo CNOT3 variants from the 2017 Deciphering Developmental Disorders Study report and nine previously unpublished individuals with de novo CNOT3 variants in Martin et al., 2019 found that eight individuals presented with either autism, autism spectrum disorder, or PDD-NOS.

1/1/2019
2S
icon
2S

Decreased from 2S to 2S

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. Resequencing of 64 candidate neurodevelopmental disorder risk genes by molecular inversion probes in ORoak et al., 2014 identified a third de novo LoF variant in the CNOT3 gene in an ASD proband from The Autism Simplex Collection (TASC).

10/1/2018
3S
icon
2S

Decreased from 3S to 2S

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. Resequencing of 64 candidate neurodevelopmental disorder risk genes by molecular inversion probes in ORoak et al., 2014 identified a third de novo LoF variant in the CNOT3 gene in an ASD proband from The Autism Simplex Collection (TASC).

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.
Submit New Gene

Report an Error

SFARI Gene Update

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.
Close