NDUFS4

NADH:ubiquinone oxidoreductase subunit S4, the group of NADH:ubiquinone oxidoreductase supernumerary subunits

Basic information

Region (hg38): 5:53560633-53683338

Links

ENSG00000164258

∙ NCBI:4724 ∙ OMIM:602694 ∙ HGNC:7711 ∙ Uniprot:O43181 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

Leigh syndrome (Definitive), mode of inheritance: AR
mitochondrial complex I deficiency, nuclear type (Moderate), mode of inheritance: AR
mitochondrial complex I deficiency (Supportive), mode of inheritance: AR
Leigh syndrome with leukodystrophy (Supportive), mode of inheritance: AR
mitochondrial complex I deficiency, nuclear type 1 (Strong), mode of inheritance: AR
Leigh syndrome (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Mitochondrial complex I deficiency, nuclear type 1; Leigh syndrome	AR	General	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	Biochemical; Cardiovascular; Gastrointestinal; Neurologic; Ophthalmologic	9463323; 10944442; 11743516; 11181577; 12616398; 16478720; 19107570; 19364667; 22326555
Medical treatment (eg, riboflavin, ubiquinol) may be beneficial; Individuals may have cardiac involvement

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NDUFS4 gene.

not_provided (145 variants)
Mitochondrial_complex_I_deficiency,_nuclear_type_1 (49 variants)
Inborn_genetic_diseases (30 variants)
Leigh_syndrome (29 variants)
not_specified (11 variants)
Mitochondrial_complex_I_deficiency (4 variants)
NDUFS4-related_disorder (4 variants)
Mitochondrial_disease (1 variants)
See_cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NDUFS4 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000002495.4. Only rare variants are included in the table.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUSVUS	Likely benignLB	BenignB	Sum
synonymous		1 clinvar	1 clinvar	46 clinvar		48
missense		1 clinvar	45 clinvar	6 clinvar		52
nonsense	7 clinvar	6 clinvar	1 clinvar			14
start loss			3			3
frameshift	7 clinvar	16 clinvar	1 clinvar			24
splice donor/acceptor (+/-2bp)	3 clinvar	7 clinvar				10
Total	17	31	51	52	0

Highest pathogenic variant AF is 0.000050875

Loading clinvar variants...

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NDUFS4	protein_coding	protein_coding	ENST00000296684	5	122706

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.000312	0.822	125702	0	39	125741	0.000155

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.842	114	91.3	1.25	0.00000434	1137
Missense in Polyphen		35	28.913	1.2105		360
Synonymous	-1.55	42	31.0	1.35	0.00000146	330
Loss of Function	1.20	7	11.4	0.616	6.67e-7	116

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000177	0.000177
Ashkenazi Jewish	0.000199	0.000198
East Asian	0.0000544	0.0000544
Finnish	0.000231	0.000231
European (Non-Finnish)	0.000176	0.000176
Middle Eastern	0.0000544	0.0000544
South Asian	0.000196	0.000196
Other	0.00	0.00

dbNSFP

Source: dbNSFP

Function: FUNCTION: Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be 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:12611891, ECO:0000269|PubMed:9463323}.;
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:10944442, ECO:0000269|PubMed:11181577, ECO:0000269|PubMed:9463323}. 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:10944442, ECO:0000269|PubMed:12616398, ECO:0000269|PubMed:19107570, ECO:0000269|PubMed:19364667}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Pathway: 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);Oxidative phosphorylation - Homo sapiens (human);Parkinson,s disease - Homo sapiens (human);Metformin Pathway, Pharmacodynamic;Electron Transport Chain;Oxidative phosphorylation;Respiratory electron transport;The citric acid (TCA) cycle and respiratory electron transport;Metabolism;Complex I biogenesis;Respiratory electron transport, ATP synthesis by chemiosmotic coupling, and heat production by uncoupling proteins. (Consensus)

Recessive Scores

pRec: 0.108

Intolerance Scores

loftool: 0.671
rvis_EVS: -0.6
rvis_percentile_EVS: 17.75

Haploinsufficiency Scores

pHI: 0.377
hipred: N
hipred_score: 0.204
ghis: 0.636

Essentials

essential_gene_CRISPR: N
essential_gene_CRISPR2: N
essential_gene_gene_trap: N
gene_indispensability_pred: N
gene_indispensability_score: 0.467

Gene Damage Prediction

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

Mouse Genome Informatics

Gene name: Ndufs4
Phenotype: respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); vision/eye phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); skeleton phenotype; cellular phenotype; immune system phenotype; homeostasis/metabolism phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; muscle phenotype;

Gene ontology

Biological process: regulation of protein phosphorylation;mitochondrial electron transport, NADH to ubiquinone;brain development;cAMP-mediated signaling;mitochondrial respiratory chain complex I assembly;cellular respiration;positive regulation of fibroblast proliferation;response to cAMP;reactive oxygen species metabolic process
Cellular component: mitochondrion;mitochondrial inner membrane;mitochondrial respiratory chain complex I
Molecular function: NADH dehydrogenase (ubiquinone) activity