GMNN

Chr 6AD

geminin DNA replication inhibitor

Also known as: Gem, MGORS6

NCBI Gene: 51053 ENSG00000112312 UniProt: O75496 OMIM: 602842

The protein geminin inhibits DNA replication by preventing incorporation of the MCM complex into pre-replication complexes and is degraded during mitosis to permit replication in the next cell cycle. Mutations in this gene cause Meier-Gorlin syndrome, a primordial dwarfism disorder characterized by severe growth restriction, microtia, absent or small patellae, and additional skeletal anomalies, inherited in an autosomal recessive pattern. The gene shows moderate tolerance to loss-of-function variants (LOEUF 0.825), consistent with the recessive inheritance pattern observed in affected individuals.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a protein that plays a critical role in cell cycle regulation. The encoded protein inhibits DNA replication by binding to DNA replication factor Cdt1, preventing the incorporation of minichromosome maintenance proteins into the pre-replication complex. The encoded protein is expressed during the S and G2 phases of the cell cycle and is degraded by the anaphase-promoting complex during the metaphase-anaphase transition. Increased expression of this gene may play a role in several malignancies including colon, rectal and breast cancer. Alternatively spliced transcript variants have been observed for this gene, and two pseudogenes of this gene are located on the short arm of chromosome 16. [provided by RefSeq, Oct 2011]

OMIM ResearchGenerating clinical summary…

GOFmechanismADLOEUF 0.821 OMIM phenotype

Clinical Summary— GMNN

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Gene-Disease Validity (ClinGen)

Meier-Gorlin syndrome 6 · ADModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.32) despite low pLI — interpret in context.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.82LOEUF

pLI 0.115

Z-score 1.93

OE 0.32 (0.14–0.82)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.99Z-score

OE missense 0.73 (0.60–0.88)

76 obs / 104.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.32 (0.14–0.82)

0≤0.351.4

Missense OE?0.73 (0.60–0.88)

0≤0.61.4

Synonymous OE?0.85

0≤1.21.6

LoF obs/exp: 3 / 9.4Missense obs/exp: 76 / 104.5Syn Z: 0.73

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongGMNN-related primordial dwarfism associated with Meier-Gorlin syndromeGOFAD

This gene — mechanism propensity

0.74top 25%

GOF

0.2796th %ile

LOF

0.3549th %ile

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

DNprediction above median

GOF1 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

GOFIn conclusion, we describe an autosomal-dominant form of MGS resulting from de novo heterozygous mutations in GMNN, likely caused by a gain-of-function mechanism in replication inhibitor geminin.1

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

References