NOL3

Chr 16AD

nucleolar protein 3

Also known as: ARC, FCM, MYOCL1, MYP, NOP, NOP30

NCBI Gene: 8996 ENSG00000140939 UniProt: O60936 OMIM: 605235

This protein functions as an anti-apoptotic factor that down-regulates caspase 2, caspase 8, and p53 enzyme activities, and may also be involved in RNA splicing. Mutations cause familial myoclonus type 1, which follows autosomal dominant inheritance. The gene is not highly constrained against loss-of-function variants, suggesting tolerance to protein truncation.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes an anti-apoptotic protein that has been shown to down-regulate the enzyme activities of caspase 2, caspase 8 and tumor protein p53. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2010]

OMIM ResearchGenerating clinical summary…

GOFmechanismADLOEUF 1.621 OMIM phenotype

Clinical Summary— NOL3

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

43 VUS of 72 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.62LOEUF

pLI 0.000

Z-score 0.37

OE 0.85 (0.46–1.62)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.13Z-score

OE missense 1.03 (0.90–1.19)

131 obs / 126.9 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.85 (0.46–1.62)

0≤0.351.4

Missense OE?1.03 (0.90–1.19)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 6 / 7.1Missense obs/exp: 131 / 126.9Syn Z: 0.65

This gene — mechanism propensity

0.4983th %ile

GOF

0.84top 5%

LOF

0.2581th %ile

The highest-scoring mechanism for this gene is gain-of-function.

GOFprediction above median · 1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFInstead, it seems more plausible that NOL3 mutation causes FCM by a gain-of-function or neomorphic mechanism, although at this time the exact mechanistic link between NOL3 and neuronal hyperexcitability remains speculative.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 22926851 ↗

ClinVar Variant Classifications

72 submitted variants in ClinVar

ClinVar

Classification Summary

VUS43

Likely Benign19

Benign3

Conflicting1

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	2	40	1	0	43
Likely Benign	0	15	2	2	19
Benign	0	0	2	1	3
Conflicting	—				1
Total	2	55	5	3	66

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

25 pathogenic / likely-pathogenic (of 37) ClinVar copy-number / structural variants overlap NOL3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →