ATP5F1A

ATP synthase F1 subunit alpha, the group of ATPase F1/V1 alpha/A and beta/B subunit family|Mitochondrial complex V: ATP synthase subunits

Basic information

Region (hg38): 18:46080248-46104334

Previous symbols: [ "ATP5AL2", "ATPM", "ATP5A1" ]

Links

ENSG00000152234 ∙ NCBI:498 ∙ OMIM:164360 ∙ HGNC:823 ∙ Uniprot:P25705 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• mitochondrial proton-transporting ATP synthase complex deficiency (Supportive), mode of inheritance: AR
• mitochondrial disease (Moderate), mode of inheritance: AR
• mitochondrial complex V (ATP synthase) deficiency, nuclear type 4B (Strong), mode of inheritance: AR
• combined oxidative phosphorylation deficiency 22 (Limited), mode of inheritance: Unknown
• mitochondrial complex V (ATP synthase) deficiency, nuclear type 4A (Strong), mode of inheritance: AD
• mitochondrial complex V (ATP synthase) deficiency, nuclear type 4A (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4A; Combined oxidative phosphorylation deficiency 22; Mitochondrial complex V (ATP synthase) deficiency, nuclear type 4B, encephalopathic type	AD/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	Audiologic/Otolaryngologic; Biochemical; Cardiovascular; Musculoskeletal; Neurologic	23596069; 23599390; 34483339; 34954817

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ATP5F1A gene.

• not_provided (182 variants)
• Inborn_genetic_diseases (45 variants)
• not_specified (17 variants)
• ATP5F1A-related_disorder (12 variants)
• Mitochondrial_complex_V_(ATP_synthase)_deficiency,_nuclear_type_4A (8 variants)
• Combined_oxidative_phosphorylation_deficiency_22 (5 variants)
• Mitochondrial_complex_V_(ATP_synthase)_deficiency,_nuclear_type_4B (3 variants)
• Lactic_acidosis (1 variants)
• Mitochondrial_disease (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ATP5F1A gene is commonly pathogenic or not. These statistics are base on transcript: NM_000004046.6. 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	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	45	3	49
missense	1	6	96	10	3	116
nonsense			2			2
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)		1	3			4
Total	1	7	102	55	6

Highest pathogenic variant AF is 6.8406376e-7

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ATP5F1A	protein_coding	protein_coding	ENST00000282050	12	20191

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.999	0.000545	125739	0	5	125744	0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.44	205	329	0.622	0.0000191	3547
Missense in Polyphen		52	156.95	0.33131		1714
Synonymous	-0.444	126	120	1.05	0.00000678	1163
Loss of Function	4.55	1	26.1	0.0384	0.00000142	307

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.0000353	0.0000352
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Mitochondrial membrane ATP synthase (F(1)F(0) ATP synthase or Complex V) produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of the respiratory chain. F-type ATPases consist of two structural domains, F(1) - containing the extramembraneous catalytic core, and F(0) - containing the membrane proton channel, linked together by a central stalk and a peripheral stalk. During catalysis, ATP synthesis in the catalytic domain of F(1) is coupled via a rotary mechanism of the central stalk subunits to proton translocation. Subunits alpha and beta form the catalytic core in F(1). Rotation of the central stalk against the surrounding alpha(3)beta(3) subunits leads to hydrolysis of ATP in three separate catalytic sites on the beta subunits. Subunit alpha does not bear the catalytic high-affinity ATP-binding sites (By similarity). {ECO:0000250, ECO:0000269|PubMed:10077593, ECO:0000269|PubMed:19285951}.
• Disease: DISEASE: Combined oxidative phosphorylation deficiency 22 (COXPD22) [MIM:616045]: A mitochondrial disorder characterized by intrauterine growth retardation, microcephaly, hypotonia, pulmonary hypertension, failure to thrive, encephalopathy, and heart failure. {ECO:0000269|PubMed:23596069}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Mitochondrial complex V deficiency, nuclear 4 (MC5DN4) [MIM:615228]: A mitochondrial disorder with heterogeneous clinical manifestations including dysmorphic features, psychomotor retardation, hypotonia, growth retardation, cardiomyopathy, enlarged liver, hypoplastic kidneys and elevated lactate levels in urine, plasma and cerebrospinal fluid. {ECO:0000269|PubMed:23599390}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Alzheimer,s disease - Homo sapiens (human);Huntington,s disease - Homo sapiens (human);Thermogenesis - Homo sapiens (human);Doxorubicin Pathway (Cardiomyocyte Cell), Pharmacodynamics;Oxidative phosphorylation - Homo sapiens (human);Parkinson,s disease - Homo sapiens (human);Mitochondrial Electron Transport Chain;Electron Transport Chain;Oxidative phosphorylation;adenosine ribonucleotides <i>de novo</i> biosynthesis;Metabolism of proteins;Formation of ATP by chemiosmotic coupling;The citric acid (TCA) cycle and respiratory electron transport;Purine metabolism;Metabolism;superpathway of purine nucleotide salvage;Mitochondrial protein import;Cristae formation;Mitochondrial biogenesis;Respiratory electron transport, ATP synthesis by chemiosmotic coupling, and heat production by uncoupling proteins.;purine nucleotides <i>de novo</i> biosynthesis;Organelle biogenesis and maintenance (Consensus)

Recessive Scores

• pRec: 0.584

Intolerance Scores

• rvis_EVS: -0.38
• rvis_percentile_EVS: 27.88

Haploinsufficiency Scores

• pHI: 0.273
• hipred: Y
• hipred_score: 0.783
• ghis: 0.583

Essentials

• essential_gene_gene_trap: E

Mouse Genome Informatics

• Gene name: Atp5a1
• Phenotype: neoplasm; growth/size/body region phenotype

Gene ontology

• Biological process: negative regulation of endothelial cell proliferation;lipid metabolic process;ATP biosynthetic process;response to oxidative stress;ATP synthesis coupled proton transport;electron transport chain;cristae formation;mitochondrial ATP synthesis coupled proton transport;positive regulation of blood vessel endothelial cell migration;ATP metabolic process;ATP hydrolysis coupled cation transmembrane transport
• Cellular component: mitochondrial proton-transporting ATP synthase complex, catalytic core F(1);mitochondrion;mitochondrial inner membrane;mitochondrial proton-transporting ATP synthase complex;mitochondrial matrix;plasma membrane;COP9 signalosome;membrane;myelin sheath;proton-transporting ATP synthase complex;extracellular exosome
• Molecular function: RNA binding;protein binding;ATP binding;ATPase activity;transmembrane transporter activity;MHC class I protein binding;ADP binding;angiostatin binding;proton-transporting ATP synthase activity, rotational mechanism