RNF112

Chr 17

ring finger protein 112

ENSG00000128482 UniProt: Q9ULX5 OMIM: 601237

The protein functions as an E3 ubiquitin-protein ligase that regulates neuronal differentiation, neurogenesis, and gliogenesis during brain development, and maintains neural functions and dendritic spine density in the adult brain. Mutations cause autosomal recessive neurodevelopmental disorder with progressive microcephaly, seizures, and brain atrophy. The gene has low constraint against loss-of-function variants, consistent with the recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, UniProt

E3 ubiquitin-protein ligase that plays an important role in neuronal differentiation, including neurogenesis and gliogenesis, during brain development. During embryonic development initiates neuronal differentiation by inducing cell cycle arrest at the G0/G1 phase through up-regulation of cell-cycle regulatory proteins (PubMed:28684796). Plays a role not only in the fetal period during the development of the nervous system, but also in the adult brain, where it is involved in the maintenance of neural functions and protection of the nervous tissue cells from oxidative stress-induced damage. Exhibits GTPase and E3 ubiquitin-protein ligase activities. Regulates dendritic spine density and synaptic neurotransmission; its ability to hydrolyze GTP is involved in the maintenance of dendritic spine density (By similarity)

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.54

Clinical Summary— RNF112

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.30) despite low pLI — interpret in context.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.54LOEUF

pLI 0.022

Z-score 3.35

OE 0.30 (0.17–0.54)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.50Z-score

OE missense 0.78 (0.71–0.86)

298 obs / 380.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.30 (0.17–0.54)

0≤0.351.4

Missense OE?0.78 (0.71–0.86)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 8 / 26.7Missense obs/exp: 298 / 380.2Syn Z: -0.56

This gene — mechanism propensity

0.7035th %ile

GOF

0.78top 25%

LOF

0.2678th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

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.

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