NONO

protein-coding

non-POU domain containing octamer binding, the group of RNA binding motif containing|Protein phosphatase 1 regulatory subunits

Gene summary

This gene encodes an RNA-binding protein which plays various roles in the nucleus, including transcriptional regulation and RNA splicing. A rearrangement between this gene and the transcription factor E3 gene has been observed in papillary renal cell carcinoma. Alternatively spliced transcript variants have been described. Pseudogenes exist on Chromosomes 2 and 16. [provided by RefSeq, Feb 2009]

MANE transcript

NM_007363.5

Inheritance

ClinVar variants

P:38U:142B:43

Top phenotype

Intellectual developmental disorder, X-linked, syndrome 34

gnomAD constraint

pLI —, LoF o/e 0.05

Max pathogenic AF

—

Genomic locus

chrX:71,254,814-71,301,522

External References & Databases

Ensembl (ENSG00000147140)

Transcript & Mutation Effects

hg38 • Region Span ~46.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0700092

Submitter: Ambry Genetics

intellectual developmental disorder, X-linked, syndromic 34STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010501

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder, X-linked, syndromic 34STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010501

Submitter: PanelApp Australia

X-linked syndromic intellectual disabilityDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0020119

Submitter: ClinGen

*NONO* was first reported in relation to X-linked syndromic intellectual disability in 2015 (Mircsof *et al*., PMID: 26571461). Common phenotypes include global developmental delay, relative macrocephaly, corpus callosum anomalies, non-compaction ventricular cardiomyopathy, dysmorphic facies, and hypotonia. At least 15 variants have been reported in 19 male probands which are included in this curation (PMIDs: 26571461, 27329731, 27550220, 30773818, 31883306, 34549882, 36426740, 36653413). Most reported variants are truncating (nonsense, frameshift and splicing), including several recurrent variants. Additionally, a Xq13.1 deletion involving the first three coding exons of *NONO* was described in one male. A recurrent missense variant leading to mild loss-of-function was reported in two families (PMID: 36894578). Both *de novo* and maternally inherited variants have been described. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is known to be loss-of-function. This gene-disease relationship is also supported by *Nono*-deficient mice which have a flattened nose, mimicking the facial anomalies observed in patients, and a smaller cerebellum, also observed in patients (PMID: 26571461). Mutant mice showed impaired learning and memory, anxiety-like behavior, and defects at inhibitory synapses, where *Nono* regulates synaptic transcription (PMID: 26571461). In summary, there is definitive evidence to support the relationship between *NONO* and X-linked syndromic intellectual disability. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on April 5, 2023 (SOP Version 9).

intellectual developmental disorder, X-linked, syndromic 34STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010501

Submitter: G2P

intellectual developmental disorder, X-linked, syndromic 34SUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010501

Submitter: Orphanet

Clinical Genomic Database (CGD)

Intellectual developmental disorder, X-linked, syndrome 34XL

Manifestation: Craniofacial; 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: 26571461

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NONO variants in ClinVar

12 Conditions Cataloged

not providedTotal: 174

Syndromic X-linked intellectual disability 34Total: 32

not specifiedTotal: 28

Inborn genetic diseasesTotal: 17

NONO-related disorderTotal: 14

See casesTotal: 2

Abnormal heart morphologyTotal: 1

Non-ossifying fibromas with pathologic factures and X-linked intellectual disabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_007363.5. 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	1 clinvar		8 clinvar	38 clinvar	2 clinvar	49
missense	1 clinvar	1 clinvar	111 clinvar	3 clinvar		116
nonsense	5 clinvar	2 clinvar	5 clinvar			12
start loss						0
frameshift	12 clinvar	5 clinvar	1 clinvar			18
splice donor/acceptor (+/-2bp)	4 clinvar	7 clinvar	17 clinvar			28
Total	23	15	142	41	2	223

Highest pathogenic variant AF is 0.00000888881

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 103 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_007363.5	RefSeq	NP_031389.3	10	MANE Select
ENST00000276079.13	Ensembl	ENSP00000276079.8	10	MANE Select
NM_001145408.2	RefSeq	NP_001138880.1	10	Standard
NM_001145409.2	RefSeq	NP_001138881.1	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

mRNA Processing
antisense pathway
AndrogenReceptor
Circadian rhythm pathway

Biological Process

activation of innate immune response
DNA repair
DNA recombination
regulation of transcription by RNA polymerase II
mRNA processing

Molecular Function

transcription regulatory region sequence-specific DNA binding
RNA polymerase II distal enhancer sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
chromatin binding
RNA binding

Cellular Component

nucleus
nucleoplasm
nucleolus
membrane
nuclear matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000276079
Coding exons: 10
Length: 17977
Individuals with no LoFs: 116649
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 116650
p: 0.00000429

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.59	52	192	0.271	0.0000164	3101
Missense (PolyPhen)		3	22.101	0.13574		493
Synonymous	0.321	54	57.1	0.946	0.00000412	879
Loss of Function	3.87	1	19.4	0.0515	0.00000179	281

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000038	0.000030	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: DNA- and RNA binding protein, involved in several nuclear processes. Binds the conventional octamer sequence in double-stranded DNA. Also binds single-stranded DNA and RNA at a site independent of the duplex site. Involved in pre-mRNA splicing, probably as a heterodimer with SFPQ. Interacts with U5 snRNA, probably by binding to a purine-rich sequence located on the 3' side of U5 snRNA stem 1b. Together with PSPC1, required for the formation of nuclear paraspeckles. The SFPQ-NONO heteromer associated with MATR3 may play a role in nuclear retention of defective RNAs. The SFPQ-NONO heteromer may be involved in DNA unwinding by modulating the function of topoisomerase I/TOP1. The SFPQ-NONO heteromer may be involved in DNA non-homologous end joining (NHEJ) required for double-strand break repair and V(D)J recombination and may stabilize paired DNA ends. In vitro, the complex strongly stimulates DNA end joining, binds directly to the DNA substrates and cooperates with the Ku70/G22P1-Ku80/XRCC5 (Ku) dimer to establish a functional preligation complex. NONO is involved in transcriptional regulation. The SFPQ-NONO-NR5A1 complex binds to the CYP17 promoter and regulates basal and cAMP- dependent transcriptional activity. NONO binds to an enhancer element in long terminal repeats of endogenous intracisternal A particles (IAPs) and activates transcription. Regulates the circadian clock by repressing the transcriptional activator activity of the CLOCK-ARNTL/BMAL1 heterodimer. Important for the functional organization of GABAergic synapses. Plays a specific and important role in the regulation of synaptic RNAs and GPHN/gephyrin scaffold structure, through the regulation of GABRA2 transcript. Plays a role in the regulation of DNA virus-mediated innate immune response by assembling into the HDP-RNP complex, a complex that serves as a platform for IRF3 phosphorylation and subsequent innate immune response activation through the cGAS- STING pathway (PubMed:28712728). {ECO:0000250|UniProtKB:Q99K48, ECO:0000269|PubMed:10858305, ECO:0000269|PubMed:11525732, ECO:0000269|PubMed:11897684, ECO:0000269|PubMed:15590677, ECO:0000269|PubMed:22416126, ECO:0000269|PubMed:26571461, ECO:0000269|PubMed:28712728}.;
Disease: DISEASE: Note=A chromosomal aberration involving NONO may be a cause of papillary renal cell carcinoma (PRCC). Translocation t(X;X)(p11.2;q13.1) with TFE3. {ECO:0000269|PubMed:9393982}.; DISEASE: Mental retardation, X-linked, syndromic, 34 (MRXS34) [MIM:300967]: A mental retardation syndrome characterized by intellectual deficit, delayed psychomotor development, poor speech, and dysmorphic features. Mental retardation is defined by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. {ECO:0000269|PubMed:26571461}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.546

Intolerance Scores

LoFtool: 0.624
RVIS EVS: 0.1
RVIS percentile EVS: 61.28

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.914

Gene Damage Prediction

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