NDUFB9
protein-codingNADH:ubiquinone oxidoreductase subunit B9, the group of NADH:ubiquinone oxidoreductase supernumerary subunits|LYR motif containing
Gene summary
The protein encoded by this gene is a subunit of the mitochondrial oxidative phosphorylation complex I (nicotinamide adenine dinucleotide: ubiquinone oxidoreductase). Complex I is localized to the inner mitochondrial membrane and functions to dehydrogenate nicotinamide adenine dinucleotide and to shuttle electrons to coenzyme Q. Complex I deficiency is the most common defect found in oxidative phosphorylation disorders and results in a range of conditions, including lethal neonatal disease, hypertrophic cardiomyopathy, liver disease, and adult-onset neurodegenerative disorders. Pseudogenes of this gene are found on chromosomes five, seven and eight. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2015]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~41.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: Unknown
Disease ID:MONDO:0032628
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0044970
Submitter: ClinGen
The relationship between *NDUFB9* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of May 20, 2024. The *NDUFB9* gene encodes NADH:ubiquinone oxidoreductase (complex I) subunit B9, which is essential for complex I activity and assembly. Defects of this protein lead to complex I deficiency. The *NDUFB9* gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2012 (PMID: 22200994). *NDUFB9* has been associated with a single disease entity to date; mitochondrial complex I deficiency, nuclear type 24 [OMIM#618245]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and is considered a primary mitochondrial disease. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included one homozygous missense identified in one case from one publication (PMID: 22200994; Patient 35838). This case was noted to have complex I deficiency in fibroblasts and a clinical presentation consistent with primary mitochondrial disease, however additional clinical details were not provided. Of note, several cases were excluded from this curation due to the variant allele frequency in the general population (PMID: 38129218) and lack of segregation and no second variant identified (PMID: 22200994; Patient 33027). A case was also reported as part of a thesis (http://theses.ncl.ac.uk/jspui/handle/10443/5044) however this was excluded as the case was not published in a peer-reviewed journal. The mechanism of disease is loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 33340416) and functional alteration studies in non-patient cells (PMID: 27626371). 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 May 20, 2024 (SOP Version 10).
Inheritance Pattern: AR
Disease ID:MONDO:0032628
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0032628
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0100133
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Biochemical; 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 NDUFB9 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005005.3. 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 | 21 | 1 | 22 | |||
| missense | 1 | 50 | 6 | 57 | ||
| nonsense | 1 | 1 | ||||
| start loss | 1 | 1 | ||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 3 | 3 | ||||
| Total | 1 | 1 | 55 | 27 | 1 | 85 |
Highest pathogenic variant AF is 0.00015488469
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_004996.1 | 4 | MANE Select | |
| Ensembl | ENSP00000276689.3 | 4 | MANE Select | |
| RefSeq | NP_001265574.1 | 3 | Standard | |
| RefSeq | NP_001265575.1 | 3 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Retrograde endocannabinoid signaling - Homo sapiens (human)
- Non-alcoholic fatty liver disease (NAFLD) - Homo sapiens (human)
- Alzheimer,s disease - Homo sapiens (human)
- Huntington,s disease - Homo sapiens (human)
- Thermogenesis - Homo sapiens (human)
Biological Process
- mitochondrial electron transport, NADH to ubiquinone
- sensory perception of sound
- mitochondrial respiratory chain complex I assembly
Molecular Function
- protein binding
- NADH dehydrogenase (ubiquinone) activity
Cellular Component
- mitochondrion
- mitochondrial inner membrane
- mitochondrial respiratory chain complex I
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000276689
- Coding exons
- 4
- Length
- 29408
- Individuals with no LoFs
- 125724
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 24
- Defined
- 125748
- p
- 0.0000954
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.000386 | 104 | 104 | 1.00 | 0.00000600 | 1154 |
| Missense (PolyPhen) | 25 | 23.11 | 1.0818 | 270 | ||
| Synonymous | 0.0967 | 38 | 38.8 | 0.980 | 0.00000201 | 325 |
| Loss of Function | 1.45 | 8 | 13.8 | 0.579 | 8.63e-7 | 133 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00016 | 0.00016 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed to be not involved in catalysis. Complex I functions in the transfer of electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone. {ECO:0000269|PubMed:27626371}.;
Recessive Scores
- pRec
- 0.147
Intolerance Scores
- LoFtool
- 0.577
- RVIS EVS
- 0.26
- RVIS percentile EVS
- 70.06
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.731
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |