NDUFAF5

protein-coding

NADH:ubiquinone oxidoreductase complex assembly factor 5, the group of Seven-beta-strand methyltransferase motif containing|Mitochondrial respiratory chain complex assembly factors

Gene summary

The NADH-ubiquinone oxidoreductase complex (complex I) of the mitochondrial respiratory chain catalyzes the transfer of electrons from NADH to ubiquinone, and consists of at least 43 subunits. The complex is located in the inner mitochondrial membrane. This gene encodes a mitochondrial protein that is associated with the matrix face of the mitochondrial inner membrane and is required for complex I assembly. A mutation in this gene results in mitochondrial complex I deficiency. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

Previous symbols:

C20orf7

MANE transcript

NM_024120.5

Inheritance

ClinVar variants

P:128U:125B:166

Top phenotype

Mitochondrial complex I deficiency, nuclear type 16

gnomAD constraint

pLI —, LoF o/e 0.8

Max pathogenic AF

—

Genomic locus

chr20:13,785,007-13,821,580

External References & Databases

Ensembl (ENSG00000101247)

Transcript & Mutation Effects

hg38 • Region Span ~36.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Leigh syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between NDUFAF5 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of February 3, 2021. The NDUFAF5 gene encodes NADH:ubiquinone oxidoreductase (complex I) assembly factor 5. Defects of this protein lead to complex I deficiency. The NDUFAF5 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2010 (PMID: 19542079). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included seven unique variants identified in seven unrelated cases from four publications (PMID: 19542079, 21607760, 29581464, 30473481). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known biochemical function, expression, functional alteration in non-patient cells, functional alteration in patient cells, and animal models (PMIDs: 18940309, 25613900, 19542079, 23536703). In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed from the first proposal of the gene-disease association. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on February 3, 2021 (SOP Version 7).

mitochondrial complex I deficiency, nuclear type 16DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0032621

Submitter: Natera

mitochondrial complex I deficiency, nuclear type 16STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032621

Submitter: Ambry Genetics

mitochondrial complex I deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100133

Submitter: Orphanet

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *NDUFAF5* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of January 18, 2024. The *NDUFAF5* gene (previously known as C20orf7) encodes the NADH:ubiquinone oxidoreductase (complex I) assembly factor 5, an arginine hydroxylase involved in the assembly of complex I. Defects of this protein lead to complex I deficiency. *NDUFAF5* was first reported in relation to autosomal recessive primary mitochondrial disease in 2008 (PMID: 18940309). While various names have been given to the constellation of features seen in those with *NDUFAF5*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *NDUFAF5* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, *NDUFAF5* was first curated by this GCEP for its association with Leigh syndrome spectrum (LSS) on February 3, 2021 (SOP v7), with a final classification of Definitive. The scope of this current curation encompassed cases of primary mitochondrial disease, which includes cases with LSS. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 11 variants (eight unique missense variants including an Ashkenazi founder variant c.749G>T; p.Gly250Val; ClinVar Variation ID: 372253; two intronic variants, and a four-nucleotide deletion expected to result in protein truncation) in 11 probands from eight publications (PMIDs: 18940309, 19542079, 21607760, 29581464, 34797029, 36580434, 30473481). The condition was first described in a patient with neonatal lactic acidosis and agenesis of the corpus callosum who died of cardiopulmonary arrest. Subsequent reported patients also had Leigh syndrome, optic atrophy, and myopathy, and some individuals had clinical features consistent with Leber Hereditary Optic Neuropathy and intellectual disability (PMIDs: 19542079, 21607760, 29581464, 34797029, 36580434, 30473481). Additional cases are reported in the literature, but maximum case scoring was reached. The mechanism of disease is loss of function. This gene-disease association is also supported by its known biochemical function in mitochondrial complex I shared by more than 10 other genes also associated with primary mitochondrial disease, expression of *NDUFAF5* in brain tissue, and model studies in *Dictyostelium* and in MCH58 Cells (PMIDs: 28797839, 25613900, 23536703, 18940309). In summary, there is definitive evidence to support the relationship between *NDUFAF5* and primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on January 18, 2024 (SOP Version 10).

mitochondrial complex I deficiency, nuclear type 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032608

Submitter: PanelApp Australia

mitochondrial complex I deficiency, nuclear type 16STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032621

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Mitochondrial complex I deficiency, nuclear type 16AR

Manifestation: Biochemical; Cardiovascular; Gastrointestinal; Neurologic; Ophthalmologic

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

Comments: Medical treatment (eg, riboflavin, ubiquinol) may be beneficial; Individuals may have cardiac involvement

Refs: 11743516; 18940309; 19542079; 21607760; 29581464; 30473481

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NDUFAF5 variants in ClinVar

10 Conditions Cataloged

not providedTotal: 445

Mitochondrial complex I deficiency, nuclear type 16Total: 95

Mitochondrial complex I deficiencyTotal: 92

Inborn genetic diseasesTotal: 55

not specifiedTotal: 47

Leigh syndromeTotal: 37

NDUFAF5-related disorderTotal: 14

Mitochondrial complex I deficiency, nuclear type 1Total: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_024120.5. 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			2 clinvar	152 clinvar	3 clinvar	157
missense	3 clinvar	16 clinvar	118 clinvar	11 clinvar		148
nonsense	5 clinvar	15 clinvar	2 clinvar			22
start loss	4 clinvar	3 clinvar				7
frameshift	16 clinvar	34 clinvar	2 clinvar			52
splice donor/acceptor (+/-2bp)	1 clinvar	31 clinvar	1 clinvar			33
Total	29	99	125	163	3	419

Highest pathogenic variant AF is 0.00047199594

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 53 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_024120.5	RefSeq	NP_077025.2	11	MANE Select
ENST00000378106.10	Ensembl	ENSP00000367346.5	11	MANE Select
NM_001039375.3	RefSeq	NP_001034464.1	10	Standard
NM_001352403.2	RefSeq	NP_001339332.1	7	Standard

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 hydroxylation
methylation
mitochondrial respiratory chain complex I assembly
oxidation-reduction process

Molecular Function

molecular_function
protein binding
methyltransferase activity
oxidoreductase activity

Cellular Component

mitochondrion
mitochondrial inner membrane
extrinsic component of mitochondrial inner membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000378106
Coding exons: 11
Length: 33472
Individuals with no LoFs: 125668
Homozygous LoFs: 0
Heterozygous LoFs: 80
Defined: 125748
p: 0.000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.150	187	193	0.970	0.00000968	2234
Missense (PolyPhen)		48	66.581	0.72093		754
Synonymous	-0.408	74	69.7	1.06	0.00000359	659
Loss of Function	0.851	17	21.2	0.801	9.69e-7	258

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00041	0.00040	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00022	0.00022	rare
Finnish	0.000094	0.000092	rare
European (Non-Finnish)	0.00040	0.00040	rare
South Asian	0.00026	0.00026	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Arginine hydroxylase involved in the assembly of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I, MT-ND1) at early stages (PubMed:18940309, PubMed:27226634). Acts by mediating hydroxylation of 'Arg-111' of NDUFS7 (PubMed:27226634). May also have methyltransferase activity (Probable). {ECO:0000269|PubMed:18940309, ECO:0000269|PubMed:27226634, ECO:0000305}.;
Disease: DISEASE: Mitochondrial complex I deficiency (MT-C1D) [MIM:252010]: A disorder of the mitochondrial respiratory chain that causes a wide range of clinical manifestations from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. {ECO:0000269|PubMed:18940309}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Leigh syndrome (LS) [MIM:256000]: An early-onset progressive neurodegenerative disorder characterized by the presence of focal, bilateral lesions in one or more areas of the central nervous system including the brainstem, thalamus, basal ganglia, cerebellum and spinal cord. Clinical features depend on which areas of the central nervous system are involved and include subacute onset of psychomotor retardation, hypotonia, ataxia, weakness, vision loss, eye movement abnormalities, seizures, and dysphagia. {ECO:0000269|PubMed:19542079, ECO:0000269|PubMed:21607760}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.105

Intolerance Scores

RVIS EVS: -0.8
RVIS percentile EVS: 12.33

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium