NDUFAF3

protein-coding

NADH:ubiquinone oxidoreductase complex assembly factor 3, the group of Mitochondrial respiratory chain complex assembly factors

Gene summary

This gene encodes a mitochondrial complex I assembly protein that interacts with complex I subunits. Mutations in this gene cause mitochondrial complex I deficiency, a fatal neonatal disorder of the oxidative phosphorylation system. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2009]

Previous symbols:

C3orf60

MANE transcript

NM_199069.2

Inheritance

ClinVar variants

P:12U:56B:29

Top phenotype

Mitochondrial complex I deficiency, nuclear type 18

gnomAD constraint

pLI —, LoF o/e 0.51

Max pathogenic AF

—

Genomic locus

chr3:49,020,459-49,023,495

External References & Databases

Ensembl (ENSG00000178057)

Transcript & Mutation Effects

hg38 • Region Span ~3.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial complex I deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100133

Submitter: Orphanet

mitochondrial complex I deficiency, nuclear type 18MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032623

Submitter: Ambry Genetics

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *NDUFAF3* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of March 7, 2022. The *NDUFAF3* gene (previously known as *C3ORF60*) encodes the NADH:ubiquinone oxidoreductase (complex I) assembly factor 3. Defects of this protein lead to complex I deficiency. The *NDUFAF3* gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2009 (PMID: 19463981), in three unrelated families with severe neonatal lactic acidosis. While various names have been given to the constellation of features seen in those with *NDUFAF3*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *NDUFAF3* phenotype has been lumped into one disease entity according to per the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included six variants (four missense, one initiation codon, one in-frame duplication) in five cases from three publications (PMIDs: 19463981, 27986404, 29344937). Affected individuals typically presented in the neonatal period to early childhood and clinical features include Leigh syndrome spectrum (LSS), neonatal lactic acidosis, developmental regression, hypotonia, myoclonic seizures, and optic atrophy. Respiratory chain enzyme activity assays in muscle and fibroblasts revealed complex I deficiency. Loss of function resulting in a complex I assembly defect is implicated as the mechanism of disease. This gene-disease association is also supported by known biochemical function and model systems in *Caenorhabditis elegans* and *Drosophila melanogaster* (PMIDs: 27509854, 22387847, 34386730). In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed since the first proposal of the association. 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 7, 2022 (SOP Version 8).

mitochondrial complex I deficiency, nuclear type 18STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032623

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial complex I deficiency, nuclear type 18STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032623

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Mitochondrial complex I deficiency, nuclear type 18AR

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; 19463981; 37572574

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NDUFAF3 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 78

Inborn genetic diseasesTotal: 34

not specifiedTotal: 21

Mitochondrial complex I deficiency, nuclear type 1Total: 18

Mitochondrial complex I deficiency, nuclear type 18Total: 15

NDUFAF3-related disorderTotal: 4

Mitochondrial complex I deficiencyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_199069.2. 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			3 clinvar	22 clinvar		25
missense	3 clinvar	1 clinvar	50 clinvar	7 clinvar		61
nonsense		2 clinvar	1 clinvar			3
start loss	1 clinvar					1
frameshift		4 clinvar	1 clinvar			5
splice donor/acceptor (+/-2bp)	1 clinvar		1 clinvar			2
Total	5	7	56	29	0	97

Highest pathogenic variant AF is 0.0001511699

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 18 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_199069.2	RefSeq	NP_951032.1	5	MANE Select
ENST00000326925.11	Ensembl	ENSP00000323076.5	5	MANE Select
NM_199070.2	RefSeq	NP_951033.1	4	Standard
NM_199073.2	RefSeq	NP_951047.1	4	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

mitochondrial respiratory chain complex I assembly

Molecular Function

protein binding

Cellular Component

nucleus
mitochondrial inner membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000326925
Coding exons: 5
Length: 3037
Individuals with no LoFs: 125700
Homozygous LoFs: 0
Heterozygous LoFs: 48
Defined: 125748
p: 0.000191

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.494	120	106	1.14	0.00000520	1150
Missense (PolyPhen)		47	39.436	1.1918		459
Synonymous	-0.472	49	45.0	1.09	0.00000216	407
Loss of Function	1.43	5	9.85	0.508	4.40e-7	91

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00032	0.00031	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0.0024	0.0024	notable
East Asian	0	0.0	absent
Finnish	0.000053	0.000046	rare
European (Non-Finnish)	0.000089	0.000088	rare
South Asian	0.00020	0.00020	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Essential factor for the assembly of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I). {ECO:0000269|PubMed:19463981}.;
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:19463981}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.126

Intolerance Scores

LoFtool: 0.404
RVIS EVS: -0.25
RVIS percentile EVS: 35.42

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.860

Gene Damage Prediction

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