GMNN
protein-codinggeminin DNA replication inhibitor
Gene summary
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]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~11.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0014794
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0014794
Submitter: ClinGen
The *GMNN* gene is located on chromosome 6 at 6p22.3 and encodes the geminin DNA replication inhibitor, a ubiquitously expressed protein that inhibits DNA replication by binding the DNA replication factor CDT1 and preventing the incorporation of mini-chromosome maintenance proteins into the pre-replication complex. The *GMNN* gene was first reported in relation to AD Meier-Gorlin Syndrome 6 (MGS6) in 2015 (Burrage et al. 2015, PMID:26637980). Meier-Gorlin syndrome is characterized by a clinical triad of symptoms: short stature, microtia, and small or absent patellae. In addition to the MGS triad, some individuals with MGS6 have marked lumbar lordosis, failure to thrive and developmental delay and/or cognitive impairment. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Three unique de novo variants reported in three individuals with Meier-Gorlin syndrome 6 from one publication (PMID:26637980) are included in this curation. These variants include one missense, one frameshift, and one nonsense, all in the first coding exon and predicted to result in a stable truncated protein starting at Met28. The mechanism of disease is unknown but suggestive of heterozygous gain-of-function/dominant negative. Supporting experimental evidence includes protein interaction data and a cell culture model. Several genes involved in DNA replication initiation have been associated with Meier-Gorlin syndrome. The GMNN protein is an inhibitor of the DNA replication initiation complex through direct CDT1 binding. The gene-disease relationship for CDT1 with Meier-Gorlin syndrome 4 has been curated and classified as definitive for (Caillat et al. 2012, PMID:22918581). Studies on an HCT116 cell culture model expressing an N-terminus truncated GMNN protein with an interrupted destruction box sequence (met-28 start) showed increased protein stability,reduced chromatin loading of MCM complex proteins, inhibited DNA replication, and impaired cell growth (Yoshida et al. 2004, PMID:14712211). In summary, there is moderate evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date Dec 4th, 2024 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0014794
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0016817
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0014794
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Musculoskeletal; 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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GMNN variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_015895.5. 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 | 21 | 22 | |||
| missense | 1 | 44 | 10 | 3 | 58 | |
| nonsense | 1 | 1 | 2 | |||
| start loss | 0 | |||||
| frameshift | 1 | 5 | 6 | |||
| splice donor/acceptor (+/-2bp) | 4 | 4 | ||||
| Total | 2 | 1 | 55 | 31 | 3 | 92 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_056979.1 | 6 | MANE Select | |
| Ensembl | ENSP00000230056.3 | 6 | MANE Select | |
| RefSeq | NP_001238918.1 | 6 | Standard | |
| RefSeq | NP_001238919.1 | 6 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| gmnn | Danio rerio | Structure: whole organism Quality: lacks all parts of type abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- DNA Replication
- Activation of the pre-replicative complex
- Mitotic G1-G1/S phases
- DNA Replication
- G1/S Transition
Biological Process
- G1/S transition of mitotic cell cycle
- regulation of DNA replication
- negative regulation of DNA replication
- animal organ morphogenesis
- positive regulation of chromatin binding
Molecular Function
- chromatin binding
- transcription corepressor activity
- protein binding
- histone deacetylase binding
- repressing transcription factor binding
Cellular Component
- nucleus
- nucleoplasm
- cytoplasm
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000230056
- Coding exons
- 6
- Length
- 11169
- Individuals with no LoFs
- 125714
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 9
- Defined
- 125723
- p
- 0.0000358
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.991 | 76 | 105 | 0.727 | 0.00000512 | 1371 |
| Missense (PolyPhen) | 13 | 31.984 | 0.40645 | 458 | ||
| Synonymous | 0.734 | 33 | 38.8 | 0.850 | 0.00000202 | 385 |
| Loss of Function | 1.93 | 3 | 9.39 | 0.319 | 3.94e-7 | 136 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000063 | 0.000062 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00012 | 0.00011 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000053 | 0.000053 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Inhibits DNA replication by preventing the incorporation of MCM complex into pre-replication complex (pre-RC). It is degraded during the mitotic phase of the cell cycle. Its destruction at the metaphase-anaphase transition permits replication in the succeeding cell cycle.;
- Disease
- DISEASE: Meier-Gorlin syndrome 6 (MGORS6) [MIM:616835]: A form of Meier-Gorlin syndrome, a syndrome characterized by bilateral microtia, aplasia/hypoplasia of the patellae, and severe intrauterine and postnatal growth retardation with short stature and poor weight gain. Additional clinical findings include anomalies of cranial sutures, microcephaly, apparently low-set and simple ears, microstomia, full lips, highly arched or cleft palate, micrognathia, genitourinary tract anomalies, and various skeletal anomalies. While almost all cases have primordial dwarfism with substantial prenatal and postnatal growth retardation, not all cases have microcephaly, and microtia and absent/hypoplastic patella are absent in some. Despite the presence of microcephaly, intellect is usually normal. {ECO:0000269|PubMed:26637980}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.180
Intolerance Scores
- LoFtool
- 0.553
- RVIS EVS
- 0.99
- RVIS percentile EVS
- 90.52
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.706
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |