NDUFAF7
protein-codingNADH:ubiquinone oxidoreductase complex assembly factor 7, the group of Mitochondrial respiratory chain complex assembly factors|7BS protein arginine methyltranferases
Gene summary
This gene encodes an assembly factor protein which helps in the assembly and stabilization of Complex I, a large multi-subunit enzyme in the mitochondrial respiratory chain. Complex I is involved in several physiological activities in the cell, including metabolite transport and ATP synthesis. The encoded protein is a methyltransferase which methylates Arg85 of a subunit of Complex I in the early stages of its assembly. A pseudogene related to this gene is located on chromosome 8. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]
- C2orf56
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~21.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0044970
Submitter: ClinGen
The relationship between *NDUFAF7* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of May 20, 2024. The *NDUFAF7* gene encodes NADH:ubiquinone oxidoreductase (complex I) assembly factor 7 which transiently interacts with and dimethylates NDUFS2, a core subunit of mitochondrial complex I. This gene has been reported in association several phenotypes in the medical literature including high myopia (PMIDs: 28837730, 32215939, 36964802), dilated cardiomyopathy (PMID: 35414514), and leukodystrophy (PMID: 32488467). The cases with isolated high myopia were excluded from this curation as this phenotype is not concerning for a primary mitochondrial disease. The cases with dilated cardiomyopathy and leukodystrophy were excluded from this curation as there was no functional evidence to support any deleterious effect of the variants reported. Experimental evidence supporting the gene-disease relationship include biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 33340416), siRNA knockdown studies in non-patient human fibroblasts (PMID: 24838397), and morpholino knockdown studies in a zebrafish model (PMID: 24838397). In summary, the evidence supporting the relationship between *NDUFAF7* and primary mitochondrial disease has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role this gene plays in this disease. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on May 20, 2024 (SOP Version 10).
Inheritance Pattern: AD
Disease ID:MONDO:0001383
Submitter: PanelApp Australia
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to NDUFAF7 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_144736.5. 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 | 19 | 2 | 22 | ||
| missense | 1 | 77 | 5 | 4 | 87 | |
| nonsense | 2 | 2 | ||||
| start loss | 0 | |||||
| frameshift | 1 | 2 | 3 | |||
| splice donor/acceptor (+/-2bp) | 3 | 3 | ||||
| Total | 0 | 2 | 85 | 24 | 6 | 117 |
Highest pathogenic variant AF is 0.000016229511
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_653337.1 | 10 | MANE Select | |
| Ensembl | ENSP00000002125.4 | 10 | MANE Select | |
| RefSeq | NP_001077415.1 | 8 | Standard | |
| RefSeq | NP_001336953.1 | 10 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| ndufaf7 | Danio rerio | Structure: whole organism Quality: morphology abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Thermogenesis - Homo sapiens (human)
- Respiratory electron transport
- The citric acid (TCA) cycle and respiratory electron transport
- Metabolism
- Complex I biogenesis
Biological Process
- peptidyl-arginine methylation, to symmetrical-dimethyl arginine
- mitochondrial respiratory chain complex I assembly
Molecular Function
- protein binding
- methyltransferase activity
- enzyme binding
- protein-arginine omega-N symmetric methyltransferase activity
Cellular Component
- extracellular space
- mitochondrion
- mitochondrial matrix
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000002125
- Coding exons
- 10
- Length
- 21773
- Individuals with no LoFs
- 125657
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 91
- Defined
- 125748
- p
- 0.000362
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -1.05 | 283 | 237 | 1.19 | 0.0000120 | 2860 |
| Missense (PolyPhen) | 81 | 83.096 | 0.97477 | 1044 | ||
| Synonymous | -1.22 | 100 | 85.6 | 1.17 | 0.00000441 | 864 |
| Loss of Function | -0.670 | 27 | 23.5 | 1.15 | 0.00000134 | 264 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00018 | 0.00018 | rare |
| Latino/Admixed American | 0.00043 | 0.00040 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00049 | 0.00049 | rare |
| Finnish | 0.00025 | 0.00023 | rare |
| European (Non-Finnish) | 0.00041 | 0.00040 | rare |
| South Asian | 0.00039 | 0.00039 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Arginine methyltransferase involved in the assembly or stability of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I) (PubMed:20406883, PubMed:24089531, PubMed:24838397). Acts by mediating symmetric dimethylation of 'Arg-118' of NDUFS2 after it assembles into the complex I, stabilizing the early intermediate complex (PubMed:24089531). {ECO:0000269|PubMed:20406883, ECO:0000269|PubMed:24089531, ECO:0000269|PubMed:24838397}.;
- Disease
- DISEASE: Note=Defects in NDUFAF7 may be a cause of susceptibility to pathologic myopia, a genetically heterogeneous disorder characterized by extreme, familial, early-onset vision loss and described as myopia accompanied by severe deformation of the eye besides excessive elongation of the eye. {ECO:0000269|PubMed:28837730}.;
Recessive Scores
- pRec
- 0.0919
Intolerance Scores
- RVIS EVS
- -0.36
- RVIS percentile EVS
- 29.31
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- N
- Essential (gene trap)
- H
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |