GFM1
protein-codingG elongation factor mitochondrial 1
Gene summary
Eukaryotes contain two protein translational systems, one in the cytoplasm and one in the mitochondria. Mitochondrial translation is crucial for maintaining mitochondrial function and mutations in this system lead to a breakdown in the respiratory chain-oxidative phosphorylation system and to impaired maintenance of mitochondrial DNA. This gene encodes one of the mitochondrial translation elongation factors. Its role in the regulation of normal mitochondrial function and in different disease states attributed to mitochondrial dysfunction is not known. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~51.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0012191
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0012191
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0012191
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0012191
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009723
Submitter: ClinGen
The relationship between GFM1 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of December 9, 2019. The GFM1 gene encodes mitochondrial elongation factor G1 (also referred to as EFG1 or EGF1), that is one of three nuclear-encoded elongation factors and plays an important role in mitochondrial translation. The GFM1 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2007 (PMID: 17160893). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included six unique variants identified in three unrelated cases from three publications; all cases were compound heterozygous for a predicted null variant and a missense variant (PMIDs: 217160893, 23430926, 25852744). No segregation data were available. Loss of function is implicated as the mechanism of disease. Of note, this gene has also been implicated in other mitochondrial diseases (including fatal infantile hepatopathy) which will be assessed separately. This gene-disease association is also supported by known biochemical function, expression, functional alteration in patient cells, functional alteration in non-patient cells, rescue in patient cells, and rescue in animal models (PMIDs: 17160893, 18853439, 27977873, 21364917, 25852744). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel December 9, 2019 (SOP Version 7).
Inheritance Pattern: AR
Disease ID:MONDO:0012191
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Gastrointestinal; 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 GFM1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_024996.7. 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 | 10 | 258 | 2 | 270 | ||
| missense | 2 | 21 | 199 | 24 | 2 | 248 |
| nonsense | 16 | 30 | 1 | 47 | ||
| start loss | 1 | 1 | ||||
| frameshift | 33 | 65 | 1 | 99 | ||
| splice donor/acceptor (+/-2bp) | 3 | 47 | 1 | 1 | 52 | |
| Total | 54 | 164 | 212 | 283 | 4 | 717 |
Highest pathogenic variant AF is 0.00011029307
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_079272.4 | 18 | MANE Select | |
| Ensembl | ENSP00000419038.1 | 18 | MANE Select | |
| RefSeq | NP_001295093.1 | 19 | Standard | |
| RefSeq | NP_001295095.1 | 14 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- miR-targeted genes in epithelium - TarBase
- miR-targeted genes in lymphocytes - TarBase
- miR-targeted genes in muscle cell - TarBase
- Translation
- Metabolism of proteins
Biological Process
- mitochondrial translational elongation
Molecular Function
- RNA binding
- translation elongation factor activity
- GTPase activity
- protein binding
- GTP binding
Cellular Component
- mitochondrion
- mitochondrial matrix
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000486715
- Coding exons
- 18
- Length
- 48298
- Individuals with no LoFs
- 125646
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 102
- Defined
- 125748
- p
- 0.000406
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.28 | 339 | 412 | 0.823 | 0.0000213 | 4879 |
| Missense (PolyPhen) | 109 | 151.17 | 0.72104 | 1725 | ||
| Synonymous | -0.609 | 151 | 142 | 1.07 | 0.00000713 | 1461 |
| Loss of Function | 2.65 | 27 | 46.5 | 0.580 | 0.00000298 | 493 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00062 | 0.00062 | rare |
| Latino/Admixed American | 0.00012 | 0.00012 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00027 | 0.00027 | rare |
| Finnish | 0.00046 | 0.00046 | rare |
| European (Non-Finnish) | 0.00045 | 0.00045 | rare |
| South Asian | 0.00059 | 0.00059 | rare |
| Other | 0.00049 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Mitochondrial GTPase that catalyzes the GTP-dependent ribosomal translocation step during translation elongation. During this step, the ribosome changes from the pre-translocational (PRE) to the post-translocational (POST) state as the newly formed A- site-bound peptidyl-tRNA and P-site-bound deacylated tRNA move to the P and E sites, respectively. Catalyzes the coordinated movement of the two tRNA molecules, the mRNA and conformational changes in the ribosome. Does not mediate the disassembly of ribosomes from messenger RNA at the termination of mitochondrial protein biosynthesis. {ECO:0000255|HAMAP-Rule:MF_03061, ECO:0000269|PubMed:19716793}.;
- Disease
- DISEASE: Combined oxidative phosphorylation deficiency 1 (COXPD1) [MIM:609060]: A mitochondrial disease resulting in early rapidly progressive hepatoencephalopathy. {ECO:0000269|PubMed:15537906, ECO:0000269|PubMed:17160893, ECO:0000269|PubMed:21119709, ECO:0000269|PubMed:26741492}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.162
Intolerance Scores
- LoFtool
- 0.836
- RVIS EVS
- 0.62
- RVIS percentile EVS
- 83.47
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- N
- Indispensability score
- 0.408
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |