Human Gene Module / Chromosome 16 / CNOT1

CNOT1CCR4-NOT transcription complex subunit 1

SFARI Gene Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
3 / 10
Rare Variants / Common Variants
44 / 0
Aliases
CNOT1, AD-005,  CDC39,  HPE12,  NOT1,  NOT1H
Associated Syndromes
Vissers-Bodmer syndrome
Chromosome Band
16q21
Associated Disorders
DD/NDD, ASD, EP, EPS
Relevance to Autism

A de novo missense variant that was predicted to be damaging was identified in the CNOT1 gene in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). A recurrent missense variant in CNOT1 (p.Arg535Cys) has been found to result in holoprosencephaly-12 with or without pancreatic agenesis, a developmental disorder characterized by abnormal separation of the embryonic forebrain resulting in dysmorphic facial features and often, but not always, impaired neurologic development (Kruszka et al., 2019; De Franco et al., 2019). Vissers et al., 2020 reported on 39 individuals with CNOT1 variants (34 previously unreported cases and the 5 cases previously described in Kruszka et al., 2019 and De Franco et al., 2019) who presented with a clinical spectrum of intellectual disability, motor delay, speech delay, seizures, hypotonia, and behavioral problems; of the 32 individuals assessed for behavioral abnormalities, 9 presented with autism spectrum disorder.

Molecular Function

Scaffolding 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. Additional complex functions may be a consequence of its influence on mRNA expression. Its scaffolding function implies its interaction with the catalytic complex module and diverse RNA-binding proteins mediating the complex recruitment to selected mRNA 3'UTRs. Involved in degradation of AU-rich element (ARE)-containing mRNAs probably via association with ZFP36. Mediates the recruitment of the CCR4-NOT complex to miRNA targets and to the RISC complex via association with TNRC6A, TNRC6B or TNRC6C. Acts as a transcriptional repressor. Represses the ligand-dependent transcriptional activation by nuclear receptors. Involved in the maintenance of embryonic stem (ES) cell identity.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CNOT1 (10 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability Lelieveld SH et al. (2016) No -
3 Support A CCR4-NOT Transcription Complex, Subunit 1, CNOT1, Variant Associated with Holoprosencephaly Kruszka P et al. (2019) No DD
4 Support A Specific CNOT1 Mutation Results in a Novel Syndrome of Pancreatic Agenesis and Holoprosencephaly through Impaired Pancreatic and Neurological Development De Franco E et al. (2019) No Epilepsy/seizures
5 Recent Recommendation De Novo Variants in CNOT1, a Central Component of the CCR4-NOT Complex Involved in Gene Expression and RNA and Protein Stability, Cause Neurodevelopmental Delay Vissers LELM et al. (2020) No ASD
6 Support - Bertoli-Avella AM et al. (2021) No -
7 Support - Bruno LP et al. (2021) Yes -
8 Support - Zhou X et al. (2022) Yes -
9 Support - Erica Rosina et al. (2024) No -
10 Support - Axel Schmidt et al. (2024) No ID
Rare Variants   (44)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 32553196 Vissers LELM et al. (2020)
c.76C>T p.Arg26Ter stop_gained De novo - - 32553196 Vissers LELM et al. (2020)
c.97C>T p.Gln33Ter stop_gained De novo - - 32553196 Vissers LELM et al. (2020)
- - copy_number_loss De novo - Simplex 33875846 Bertoli-Avella AM et al. (2021)
c.210+1G>T - splice_site_variant De novo - - 32553196 Vissers LELM et al. (2020)
c.434-2A>G - splice_site_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.2236A>C p.Thr746Pro missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.3735+1G>T - splice_site_variant De novo - - 32553196 Vissers LELM et al. (2020)
c.3735+5G>A - splice_site_variant De novo - - 32553196 Vissers LELM et al. (2020)
c.4138-2A>C - splice_site_variant De novo - - 32553196 Vissers LELM et al. (2020)
c.5914G>A p.Gly1972Arg missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.582A>G p.Gly194%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.777G>C p.Met259Ile synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.1188T>A p.Tyr396Ter stop_gained Unknown - - 32553196 Vissers LELM et al. (2020)
c.1603C>T p.Arg535Cys missense_variant De novo - - 31006510 Kruszka P et al. (2019)
c.1924C>G p.Gln642Glu missense_variant De novo - - 32553196 Vissers LELM et al. (2020)
c.2689G>A p.Glu897Lys missense_variant De novo - - 32553196 Vissers LELM et al. (2020)
c.2698C>T p.Arg900Cys missense_variant De novo - - 32553196 Vissers LELM et al. (2020)
c.76C>T p.Arg26Ter stop_gained Familial Maternal - 32553196 Vissers LELM et al. (2020)
c.3113C>T p.Thr1038Ile missense_variant De novo - - 32553196 Vissers LELM et al. (2020)
c.3265G>C p.Val1089Leu missense_variant De novo - - 32553196 Vissers LELM et al. (2020)
c.3443T>C p.Leu1148Pro missense_variant De novo - - 32553196 Vissers LELM et al. (2020)
c.3563A>G p.Asp1188Gly missense_variant De novo - - 32553196 Vissers LELM et al. (2020)
c.3722A>G p.Lys1241Arg missense_variant De novo - - 32553196 Vissers LELM et al. (2020)
c.4255A>G p.Thr1419Ala missense_variant De novo - - 32553196 Vissers LELM et al. (2020)
c.4283T>C p.Phe1428Ser missense_variant De novo - - 32553196 Vissers LELM et al. (2020)
c.4432C>T p.Arg1478Cys missense_variant De novo - - 32553196 Vissers LELM et al. (2020)
c.4482A>T p.Gln1494His missense_variant De novo - - 32553196 Vissers LELM et al. (2020)
c.4714T>G p.Tyr1572Asp missense_variant De novo - - 32553196 Vissers LELM et al. (2020)
c.6647A>G p.Asn2216Ser missense_variant De novo - - 32553196 Vissers LELM et al. (2020)
c.102+2T>C - splice_site_variant Familial Maternal - 32553196 Vissers LELM et al. (2020)
c.1804A>G p.Thr602Ala missense_variant De novo - Simplex 34948243 Bruno LP et al. (2021)
c.4800G>C p.Lys1600Asn splice_site_variant De novo - - 32553196 Vissers LELM et al. (2020)
c.2636C>G p.Ser879Cys missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1603C>T p.Arg535Cys missense_variant De novo - Simplex 31006513 De Franco E et al. (2019)
c.2698C>T p.Arg900Cys missense_variant De novo - Simplex 27479843 Lelieveld SH et al. (2016)
c.550del p.Leu184SerfsTer20 frameshift_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.7011C>G p.Phe2337Leu missense_variant De novo - Simplex 38041506 Erica Rosina et al. (2024)
c.6303dup p.Leu2102SerfsTer4 frameshift_variant De novo - - 32553196 Vissers LELM et al. (2020)
c.608_611del p.Ile203ThrfsTer32 frameshift_variant De novo - - 32553196 Vissers LELM et al. (2020)
c.1603C>T p.Arg535Cys missense_variant Unknown Not paternal Simplex 31006513 De Franco E et al. (2019)
c.3363_3364insTAAGGTAAGCTAAA p.Val1122Ter frameshift_variant De novo - - 32553196 Vissers LELM et al. (2020)
c.3681_3687del p.Lys1227AsnfsTer7 frameshift_variant Unknown Not paternal - 32553196 Vissers LELM et al. (2020)
c.6518_6519insAAACAAAAAGGATTTGGATTCCTATCTTA p.Asp2174AsnfsTer71 frameshift_variant Familial Maternal - 32553196 Vissers LELM et al. (2020)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

Score Delta: Score remained at 2S

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.

S

Syndromic

See all Category S Genes

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."

4/1/2022
icon
2

Increased from to 2

Krishnan Probability Score

Score 0.44548167526154

Ranking 15387/25841 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 0.99999999999948

Ranking 40/18225 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 0.92439440627899

Ranking 9980/18665 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
Zhang D Score

Score 0.50851609511812

Ranking 458/20870 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
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