CNOT3

CNOT3 (HGNC: 7879) encodes the CCR4-NOT transcription complex subunit 3, which is a component of the CCR4-NOT complex. The protein plays as a global regulator of RNA polymerase II transcription. Genetic predisposition in CNOT3 have been observed in patients with ID/ASD (PMID: 31201375; 32720325; 31474762), T-cell acute lymphoblastic leukemia (PMID: 23263491), lung cancer (PMID: 31177396; PMID: 3053184), polyposis adenomas (PMID: 31231471); colorectal cancer (PMID: 2789937). Typical phenotypes of complex neurodevelopmental disorder (MONDO: 0100038) have been repeatedly observed across studies, and identical variants detected in unrelated probands inherited by autosomal dominant mechanism (HP:0000006). CNOT3 de novo missense and LOF variants, which are absent from gnomAD, have been found in patients from a DDD study (PMID: 31201375) or other study (PMID: 31474762) with identical clinical presentations of ID/ASD, hypotonia and dysmorphic features. Familial transmission of LOF variants have been observed in two families with history of ID (PMID: 32720325). Genetic evidence reached the max score of 12 points. There are no functional studies present in the literature. In summary, CNOT3 is definitively associated with complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 08/24/2021 (SOP Version 8).

intellectual developmental disorder with speech delay, autism, and dysmorphic faciesMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0032864

Submitter: Ambry Genetics

intellectual developmental disorder with speech delay, autism, and dysmorphic faciesDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0032864

Submitter: G2P

intellectual developmental disorder with speech delay, autism, and dysmorphic faciesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032864

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Intellectual developmental disorder with speech delay, autism, and dysmorphic faciesAD

Manifestation: Craniofacial; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 31201375

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CNOT3 variants in ClinVar

12 Conditions Cataloged

not providedTotal: 281

Intellectual developmental disorder with speech delay, autism, and dysmorphic faciesTotal: 103

Inborn genetic diseasesTotal: 97

not specifiedTotal: 51

CNOT3-related disorderTotal: 39

CNOT3-related disordersTotal: 6

Intellectual disabilityTotal: 5

Complex neurodevelopmental disorderTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014516.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		2 clinvar	9 clinvar	64 clinvar	5 clinvar	80
missense	1 clinvar	18 clinvar	209 clinvar	33 clinvar	2 clinvar	263
nonsense	10 clinvar	6 clinvar	2 clinvar			18
start loss						0
frameshift	25 clinvar	9 clinvar				34
splice donor/acceptor (+/-2bp)	4 clinvar	4 clinvar	3 clinvar			11
Total	40	39	223	97	7	406

Highest pathogenic variant AF is 0.000041849213

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 80 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014516.4	RefSeq	NP_055331.1	17	MANE Select
ENST00000221232.11	Ensembl	ENSP00000221232.5	17	MANE Select
NM_001440653.1	RefSeq	NP_001427582.1	17	Standard
NM_001440654.1	RefSeq	NP_001427583.1	17	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

RNA degradation - Homo sapiens (human)
Gene expression (Transcription)
Generic Transcription Pathway
RNA Polymerase II Transcription
Metabolism of RNA

Biological Process

nuclear-transcribed mRNA poly(A) tail shortening
trophectodermal cell differentiation
regulation of transcription, DNA-templated
DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest
negative regulation of translation

Molecular Function

protein binding

Cellular Component

P-body
nucleus
cytosol
CCR4-NOT complex
CCR4-NOT core complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000406403
Coding exons: 17
Length: 17976
Individuals with no LoFs: 125661
Homozygous LoFs: 0
Heterozygous LoFs: 3
Defined: 125664
p: 0.0000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.76	230	456	0.504	0.0000286	4892
Missense (PolyPhen)		31	155.47	0.1994		1650
Synonymous	-0.563	200	190	1.05	0.0000135	1445
Loss of Function	5.81	0	39.3	0.00	0.00000205	435

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000037	0.000018	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: 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. May be involved in metabolic regulation; may be involved in recruitment of the CCR4-NOT complex to deadenylation target mRNAs involved in energy metabolism. Involved in mitotic progression and regulation of the spindle assembly checkpoint by regulating the stability of MAD1L1 mRNA. Can repress transcription and may link the CCR4-NOT complex to transcriptional regulation; the repressive function may involve histone deacetylases. Involved in the maintenance of emryonic stem (ES) cell identity. {ECO:0000269|PubMed:14707134, ECO:0000269|PubMed:22342980, ECO:0000269|PubMed:22367759}.;

Recessive Scores

pRec: 0.102

Intolerance Scores

LoFtool: 0.408
RVIS EVS: -0.6
RVIS percentile EVS: 18.14

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.948

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium