SLC25A4

solute carrier family 25 member 4, the group of Solute carrier family 25

Basic information

Region (hg38): 4:185143266-185150382

Previous symbols: [ "PEO3", "PEO2", "ANT1" ]

Links

ENSG00000151729 ∙ NCBI:291 ∙ OMIM:103220 ∙ HGNC:10990 ∙ Uniprot:P12235 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• mitochondrial DNA depletion syndrome 12B (cardiomyopathic type), autosomal recessive (Moderate), mode of inheritance: AR
• progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2 (Moderate), mode of inheritance: AD
• mitochondrial DNA depletion syndrome 12A (cardiomyopathic type), autosomal dominant (Moderate), mode of inheritance: AD
• Sengers syndrome (Supportive), mode of inheritance: AR
• autosomal dominant progressive external ophthalmoplegia (Supportive), mode of inheritance: AD
• mitochondrial DNA depletion syndrome 12B (cardiomyopathic type), autosomal recessive (Strong), mode of inheritance: AR
• mitochondrial disease (Definitive), mode of inheritance: AR
• mitochondrial DNA depletion syndrome 12A (cardiomyopathic type), autosomal dominant (Strong), mode of inheritance: AD
• progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2 (Strong), mode of inheritance: AD
• mitochondrial DNA depletion syndrome 12B (cardiomyopathic type), autosomal recessive (Definitive), mode of inheritance: AR
• Leigh syndrome (Limited), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Mitochondrial DNA depletion syndrome 12A (cardiomyopathic type); Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 2; Mitochondrial DNA depletion syndrome 12B (cardiomyopathic type)	AD/AR	Cardiovascular; Endocrine	In PEO, individuals have been described with endocrinopathy (eg, thyroid dysfunctiona), and awareness may allow prompt detection and treatment; In Mitochondrial DNA depletion syndrome (cardiomyopathic type), surveillance (eg, with echocardiography/electrocardiography), preventive measures and medical management related to cardiomyopathy may decrease morbidity and mortality	Audiologic/Otolaryngologic; Cardiovascular; Endocrine; Musculoskeletal; Neurologic	10926541; 11756592; 1756613; 12112115; 12210792; 16155110; 27693233
Cardiomyopathy has only been described in an individual with a homozygous variant

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SLC25A4 gene.

• not provided (6 variants)
• Mitochondrial DNA depletion syndrome 12B (cardiomyopathic type), autosomal recessive (1 variants)
• Mitochondrial DNA depletion syndrome 12A (cardiomyopathic type), autosomal dominant (1 variants)
• Mitochondrial disease (1 variants)
• Inborn genetic diseases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SLC25A4 gene is commonly pathogenic or not.

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.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	50	2	53
missense	1	4	67	3		75
nonsense	1					1
start loss						0
frameshift	4	1	1			6
inframe indel			2			2
splice donor/acceptor (+/-2bp)						0
splice region			3	3		6
non coding			42	16	33	91
Total	6	5	113	69	35

Highest pathogenic variant AF is 0.0000197

Variants in SLC25A4

This is a list of pathogenic ClinVar variants found in the SLC25A4 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
4-185143270-C-T		Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2	Benign (Jan 13, 2018)
4-185143289-C-A		Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2	Benign (Jun 16, 2018)
4-185143308-C-T		Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2 • Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2;Mitochondrial DNA depletion syndrome 12A (cardiomyopathic type), autosomal dominant;Mitochondrial DNA depletion syndrome 12B (cardiomyopathic type), autosomal recessive	Uncertain significance (Sep 07, 2021)
4-185143327-G-A		Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2	Uncertain significance (Jan 12, 2018)
4-185143348-G-A		not specified • Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2	Benign (Nov 29, 2023)
4-185143358-C-A		not specified	Uncertain significance (Oct 29, 2023)
4-185143369-C-T		SLC25A4-related disorder	Likely benign (Jul 12, 2024)
4-185143384-C-A		not specified	Likely benign (Apr 20, 2015)
4-185143386-C-G			Uncertain significance (Oct 17, 2023)
4-185143390-G-T			Uncertain significance (Jul 25, 2022)
4-185143399-A-G			Likely benign (Mar 12, 2023)
4-185143419-G-A		Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2	Uncertain significance (Mar 25, 2024)
4-185143421-G-A			Uncertain significance (Aug 23, 2022)
4-185143423-C-A			Likely benign (Sep 01, 2021)
4-185143430-G-A			Uncertain significance (Feb 23, 2023)
4-185143431-C-T			Uncertain significance (Aug 31, 2022)
4-185143432-C-A		not specified	Likely benign (Aug 04, 2023)
4-185143437-C-A		Inborn genetic diseases	Uncertain significance (Dec 20, 2023)
4-185143444-C-G			Likely benign (Jul 20, 2023)
4-185143445-G-A		Inborn genetic diseases	Uncertain significance (Nov 07, 2023)
4-185143447-G-A			Likely benign (Nov 14, 2023)
4-185143447-G-C			Likely benign (Dec 05, 2023)
4-185143453-C-G			Likely benign (Jan 08, 2022)
4-185143453-C-T			Likely benign (Aug 01, 2022)
4-185143463-A-G			Uncertain significance (Jul 27, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SLC25A4	protein_coding	protein_coding	ENST00000281456	4	7142

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.453	0.541	125741	0	7	125748	0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.87	105	175	0.601	0.0000103	1956
Missense in Polyphen		43	99.22	0.43338		1139
Synonymous	-0.154	74	72.3	1.02	0.00000463	589
Loss of Function	2.33	2	9.90	0.202	4.23e-7	122

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000289	0.0000289
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000546	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.0000440	0.0000439
Middle Eastern	0.0000546	0.0000544
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Involved in mitochondrial ADP/ATP transport. Catalyzes the exchange of cytoplasmic ADP with mitochondrial ATP across the mitochondrial inner membrane. {ECO:0000269|PubMed:27693233}.
• Disease: DISEASE: Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 2 (PEOA2) [MIM:609283]: A disorder characterized by progressive weakness of ocular muscles and levator muscle of the upper eyelid. In a minority of cases, it is associated with skeletal myopathy, which predominantly involves axial or proximal muscles and which causes abnormal fatigability and even permanent muscle weakness. Ragged-red fibers and atrophy are found on muscle biopsy. A large proportion of chronic ophthalmoplegias are associated with other symptoms, leading to a multisystemic pattern of this disease. Additional symptoms are variable, and may include cataracts, hearing loss, sensory axonal neuropathy, ataxia, depression, hypogonadism, and parkinsonism. {ECO:0000269|PubMed:10926541, ECO:0000269|PubMed:11756613, ECO:0000269|PubMed:12112115, ECO:0000269|PubMed:12707443, ECO:0000269|PubMed:15792871, ECO:0000269|PubMed:18575922, ECO:0000269|PubMed:27693233}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Mitochondrial DNA depletion syndrome 12B, cardiomyopathic type (MTDPS12B) [MIM:615418]: An autosomal recessive mitochondrial disorder characterized by childhood onset of slowly progressive hypertrophic cardiomyopathy and generalized skeletal myopathy resulting in exercise intolerance and, in some patients, muscle weakness and atrophy. Skeletal muscle biopsy shows ragged red fibers, mtDNA depletion, and accumulation of abnormal mitochondria. {ECO:0000269|PubMed:16155110, ECO:0000269|PubMed:22187496, ECO:0000269|PubMed:25732997, ECO:0000269|PubMed:27693233}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Mitochondrial DNA depletion syndrome 12A, cardiomyopathic type (MTDPS12A) [MIM:617184]: An autosomal dominant mitochondrial disorder characterized by severe hypotonia due to mitochondrial dysfunction apparent at birth. Affected infants have respiratory insufficiency requiring mechanical ventilation and have poor or no motor development. Many die in infancy, and those that survive have profound hypotonia with significant muscle weakness and inability to walk independently. Some patients develop hypertrophic cardiomyopathy. Muscle samples show mtDNA depletion and severe combined mitochondrial respiratory chain deficiencies. {ECO:0000269|PubMed:27693233}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Benzodiazepine Pathway, Pharmacodynamics;Huntington,s disease - Homo sapiens (human);HTLV-I infection - Homo sapiens (human);Necroptosis - Homo sapiens (human);Calcium signaling pathway - Homo sapiens (human);Parkinson,s disease - Homo sapiens (human);cGMP-PKG signaling pathway - Homo sapiens (human);Cellular senescence - Homo sapiens (human);Mitochondrial Electron Transport Chain;Electron Transport Chain;Synaptic Vesicle Pathway;Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways;Disease;Vpr-mediated induction of apoptosis by mitochondrial outer membrane permeabilization;Host Interactions of HIV factors;HIV Infection;Metabolism of proteins;Infectious disease;Metabolism;Regulation of insulin secretion;AndrogenReceptor;Vitamin B9 (folate) metabolism;Mitochondrial protein import;Integration of energy metabolism;Interactions of Vpr with host cellular proteins (Consensus)

Recessive Scores

• pRec: 0.413

Intolerance Scores

• loftool: 0.172
• rvis_EVS: 0.06
• rvis_percentile_EVS: 58.26

Haploinsufficiency Scores

• pHI: 0.266
• hipred: Y
• hipred_score: 0.773
• ghis: 0.482

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.920

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Slc25a4
• 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); normal phenotype; muscle phenotype; homeostasis/metabolism phenotype; cellular phenotype

Gene ontology

• Biological process: mitochondrial genome maintenance;generation of precursor metabolites and energy;apoptotic mitochondrial changes;adenine transport;ADP transport;ATP transport;viral process;regulation of insulin secretion;transmembrane transport;negative regulation of necroptotic process
• Cellular component: mitochondrion;mitochondrial inner membrane;integral component of plasma membrane;integral component of mitochondrial membrane;myelin sheath
• Molecular function: ATP:ADP antiporter activity;protein binding;adenine transmembrane transporter activity