NDUFAF1

protein-coding

NADH:ubiquinone oxidoreductase complex assembly factor 1, the group of Mitochondrial complex I assembly complex|Mitochondrial respiratory chain complex assembly factors

Gene summary

This gene encodes a complex I assembly factor protein. Complex I (NADH-ubiquinone oxidoreductase) catalyzes the transfer of electrons from NADH to ubiquinone (coenzyme Q) in the first step of the mitochondrial respiratory chain, resulting in the translocation of protons across the inner mitochondrial membrane. The encoded protein is required for assembly of complex I, and mutations in this gene are a cause of mitochondrial complex I deficiency. Alternatively spliced transcript variants have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 19. [provided by RefSeq, Dec 2011]

MANE transcript

NM_016013.4

Inheritance

ClinVar variants

P:5U:117B:37

Top phenotype

Mitochondrial complex I deficiency, nuclear type 11

gnomAD constraint

pLI —, LoF o/e 0.46

Max pathogenic AF

—

Genomic locus

chr15:41,387,218-41,409,403

External References & Databases

Ensembl (ENSG00000137806)

Transcript & Mutation Effects

hg38 • Region Span ~22.2 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 diseaseMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *NDUFAF1* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of February 17, 2022. The *NDUFAF1* gene encodes the NADH:ubiquinone oxidoreductase (complex I) assembly factor I. Defects of this protein lead to complex I deficiency. The *NDUFAF1* gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2007 (PMID: 17557076). While various names have been given to the constellation of features seen in those with *NDUFAF1*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *NDUFAF1* 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 four variants in two cases from two publications (PMIDs: 17557076, 21931170). No segregation data were available. 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, functional alterations in patient and non-patient cells, and animal models (PMIDs: 27509854, 27626371, 18940309, 22387847, 23226344). In summary, there is moderate 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 February 17, 2022 (SOP Version 8).

mitochondrial complex I deficiency, nuclear type 11LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0032617

Submitter: Ambry Genetics

mitochondrial complex I deficiency, nuclear type 11STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032617

Submitter: PanelApp Australia

mitochondrial complex I deficiency, nuclear type 11LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0032617

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Mitochondrial complex I deficiency, nuclear type 11AR

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; 17557076; 21931170

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NDUFAF1 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 126

not specifiedTotal: 65

Mitochondrial complex I deficiency, nuclear type 1Total: 16

Mitochondrial complex I deficiency, nuclear type 11Total: 10

NDUFAF1-related disorderTotal: 4

Mitochondrial complex I deficiencyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016013.4. 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			2 clinvar	25 clinvar	2 clinvar	29
missense	1 clinvar	2 clinvar	108 clinvar	8 clinvar	2 clinvar	121
nonsense			2 clinvar			2
start loss	1 clinvar					1
frameshift	1 clinvar		2 clinvar			3
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	3	2	117	33	4	159

Highest pathogenic variant AF is 0.000029740551

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 73 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016013.4	RefSeq	NP_057097.2	4	MANE Select
ENST00000260361.9	Ensembl	ENSP00000260361.4	4	MANE Select
NM_001437486.1	RefSeq	NP_001424415.1	4	Standard
NM_001437487.1	RefSeq	NP_001424416.1	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 electron transport, NADH to ubiquinone
mitochondrial respiratory chain complex I assembly
protein-containing complex assembly

Molecular Function

protein binding
unfolded protein binding

Cellular Component

mitochondrion
mitochondrial inner membrane
mitochondrial respiratory chain complex I
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000260361
Coding exons: 4
Length: 15167
Individuals with no LoFs: 125715
Homozygous LoFs: 0
Heterozygous LoFs: 33
Defined: 125748
p: 0.000131

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.442	198	181	1.09	0.0000102	2170
Missense (PolyPhen)		65	62.583	1.0386		745
Synonymous	1.04	55	65.7	0.837	0.00000371	618
Loss of Function	1.82	6	13.1	0.458	7.11e-7	153

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000088	0.000088	rare
South Asian	0.00042	0.00042	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Chaperone protein involved in the assembly of the mitochondrial NADH:ubiquinone oxidoreductase complex (complex I). {ECO:0000250}.;

Intolerance Scores

LoFtool: 0.699
RVIS EVS: 0.58
RVIS percentile EVS: 82.17

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.626

Gene Damage Prediction

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