COX14
protein-codingcytochrome c oxidase assembly factor COX14, the group of Mitochondrial respiratory chain complex assembly factors
Gene summary
This gene encodes a small single-pass transmembrane protein that localizes to mitochondria. This protein may play a role in coordinating the early steps of cytochrome c oxidase (COX; also known as complex IV) subunit assembly and, in particular, the synthesis and assembly of the COX I subunit of the holoenzyme. Mutations in this gene have been associated with mitochondrial complex IV deficiency. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2012]
- C12orf62
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~8.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009068
Submitter: Orphanet
Inheritance Pattern: Unknown
Disease ID:MONDO:0009068
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0033639
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0044970
Submitter: ClinGen
The relationship between *COX14* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of March 21, 2022. The *COX14* gene encodes a Complex IV, or cytochrome c oxidase (COX) assembly factor and is also involved in translation of *MT-CO1*, the gene encoding the COX1 subunit of the enzyme. The *COX14* gene has been reported in relation to autosomal recessive primary mitochondrial disease in a single family in a single publication in 2012 (PMID: 22243966). While various names have been given to the constellation of features seen in those with *COX14*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *COX14* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. While segregation data were considered, the LOD score (1.68) did not meet criteria to be scored per the ClinGen Gene Curation SOP V8 (PMID: 22243966). This curation included one homozygous variant identified in one proband in one publication (PMID: 22243966). Affected individuals in this family had a severe lactic acidosis and died shortly after birth. Loss of function is suspected to be the mechanism of disease. This gene-disease association is also supported by known biochemical function, functional alteration in patient cells, functional alteration in non-patient cells, and rescue in patient cells (PMID: 22243966). In summary, there is limited 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/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on March 21, 2022 (SOP Version 8).
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Biochemical; Craniofacial; Endocrine; Gastrointestinal; Musculoskeletal; Neurologic; Ophthalmologic; Renal
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 COX14 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_032901.4. 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 | 7 | 7 | ||||
| missense | 1 | 20 | 21 | |||
| nonsense | 1 | 1 | ||||
| start loss | 1 | 1 | ||||
| frameshift | 1 | 2 | 3 | |||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 1 | 1 | 24 | 7 | 0 | 33 |
Highest pathogenic variant AF is 0.000011152983
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_116290.1 | 1 | MANE Select | |
| Ensembl | ENSP00000446524.1 | 1 | MANE Select | |
| RefSeq | NP_001244062.1 | 1 | Standard | |
| RefSeq | NP_001244063.1 | 1 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Thermogenesis - Homo sapiens (human)
- Gene expression (Transcription)
- Generic Transcription Pathway
- RNA Polymerase II Transcription
- Respiratory electron transport
Biological Process
- mitochondrial respiratory chain complex IV assembly
Cellular Component
- mitochondrion
- integral component of membrane
- mitochondrial membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000550487
- Coding exons
- 1
- Length
- 8479
- Individuals with no LoFs
- 125732
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 12
- Defined
- 125744
- p
- 0.0000477
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.0597 | 35 | 34.0 | 1.03 | 0.00000195 | 363 |
| Missense (PolyPhen) | 10 | 10.713 | 0.93343 | 134 | ||
| Synonymous | 0.513 | 10 | 12.3 | 0.814 | 6.15e-7 | 113 |
| Loss of Function | 0.769 | 0 | 0.689 | 0.00 | 2.85e-8 | 10 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.00017 | 0.00017 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| 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: Core component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, that regulates cytochrome c oxidase assembly. Requires for coordination of the early steps of cytochrome c oxidase assembly with the synthesis of MT-CO1. {ECO:0000269|PubMed:22243966, ECO:0000269|PubMed:22356826}.;
- Disease
- DISEASE: Note=Defects in COX14 may be a cause of a mitochondrial disorder presenting with severe congenital lactic acidosis and dysmorphic features associated with a COX assembly defect. Other features include brain hypertrophy, diffuse alteration of the white-matter myelination, and numerous cavities in the parieto- occipital region, brainstem, and cerebellum, as well as hepatomegaly, hypertrophic cardiomyopathy, renal hypoplasia, and adrenal-gland hyperplasia. {ECO:0000269|PubMed:22243966}.;
Intolerance Scores
- RVIS EVS
- -0.03
- RVIS percentile EVS
- 51.04
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.114
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Low | Low | Low |
| Primary Immunodeficiency | Medium | Low | Medium |
| Cancer | Low | Low | Low |