NONO

Chr X

non-POU domain containing octamer binding

Also known as: MRXS34, NMT55, NRB54, P54, P54NRB, PPP1R114

NCBI Gene: 4841 ENSG00000147140 UniProt: Q15233

This protein is a DNA- and RNA-binding protein involved in pre-mRNA splicing, transcriptional regulation, DNA repair, and nuclear paraspeckle formation. Mutations cause X-linked syndromic intellectual developmental disorder. The gene is highly constrained against loss-of-function variants (pLI 0.99, LOEUF 0.24), indicating that protein function is critical for normal development.

ResearchSummary from RefSeq, OMIM, UniProt

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]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtIntellectual developmental disorder, X-linked, syndromic 34

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · X-linked syndromic intellectual disability · XL · ClinGen 2023

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

116

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.24

LOEUF· LoF intol.

LOF

Mechanism· G2P

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.24LOEUF

pLI 0.993

Z-score 3.87

OE 0.05 (0.02–0.24)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.59Z-score

OE missense 0.27 (0.22–0.34)

52 obs / 191.9 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.05 (0.02–0.24)

0≤0.351.4

Missense OE?0.27 (0.22–0.34)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 1 / 19.4Missense obs/exp: 52 / 191.9Syn Z: 0.32

Background carrier burden — how many people carry a rare variant somewhere in NONO?

gnomAD v4 · ~732k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 610

177 rare PASS variants

Rare truncating (LoF)

1 in 4,900

30 rare PASS variants

Rare synonymous (reference)

1 in 340

101 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NONO. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~561k	1 in 810	1 in 7,100
South Asian	~36k	1 in 270	≈ 1 in 8,900
Remaining (unassigned)	~31k	1 in 540	1 in 5,800
European (Finnish)	~27k	1 in 1,900	≈ 1 in 21,000
Admixed American	~23k	1 in 350	≈ 1 in 5,400
African / African American	~21k	1 in 430	1 in 3,300
East Asian	~20k	1 in 350	1 in 3,700
Ashkenazi Jewish	~13k	1 in 680	≈ 1 in 13,000
Middle Eastern	~2,757	1 in 490	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 10 coding exons well covered in gnomAD exomes and genomes.? see exons ↓