SLC25A4

protein-coding

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

Gene summary

This gene is a member of the mitochondrial carrier subfamily of solute carrier protein genes. The product of this gene functions as a gated pore that translocates ADP from the cytoplasm into the mitochondrial matrix and ATP from the mitochondrial matrix into the cytoplasm. The protein forms a homodimer embedded in the inner mitochondria membrane. Mutations in this gene have been shown to result in autosomal dominant progressive external opthalmoplegia and familial hypertrophic cardiomyopathy. [provided by RefSeq, Jun 2013]

Previous symbols:

PEO3
PEO2
ANT1

MANE transcript

NM_001151.4

Inheritance

AR, AD

ClinVar variants

P:27U:118B:72

Top phenotype

Mitochondrial DNA depletion syndrome 12A (cardiomyopathic type); Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 2; Mitochondrial DNA depletion syndrome 12B (cardiomyopathic type)

gnomAD constraint

pLI —, LoF o/e 0.2

Max pathogenic AF

—

Genomic locus

chr4:185,143,266-185,150,382

External References & Databases

Ensembl (ENSG00000151729)

Transcript & Mutation Effects

hg38 • Region Span ~7.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial DNA depletion syndrome 12B (cardiomyopathic type), autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014175

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial DNA depletion syndrome 12A (cardiomyopathic type), autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014959

Submitter: Labcorp Genetics (formerly Invitae)

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012238

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial DNA depletion syndrome 12A (cardiomyopathic type), autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014959

Submitter: G2P

Sengers syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008922

Submitter: Orphanet

Leigh syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between SLC25A4 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of March 24, 2021. The SLC25A4 gene encodes the mitochondrial adenine nucleotide translocator located in the mitochondrial inner membrane and functions to move ADP across the inner membrane into the mitochondrial matrix and ATP from the matrix into the cytoplasm. The SLC25A4 gene has been reported only once in relation to autosomal dominant Leigh syndrome spectrum, in 2019 (PMID: 31271879). However, defects of this gene are also associated with other mitochondrial phenotypes outside the scope of the Leigh syndrome spectrum gene-disease curation, including autosomal dominant progressive external ophthalmoplegia (PEO) with or without additional features such as exercise intolerance, muscle weakness, and hearing loss; a severe autosomal dominant presentation caused by de novo variants in this gene and characterized by infantile onset encephalomyopathy; and autosomal recessive skeletal myopathy and cardiomyopathy. Evidence supporting the relationship between SLC25A4 and Leigh syndrome spectrum includes case-level data and experimental data. This curation included one de novo variant identified in one case in one publication (PMID: 31271879). No segregation data were available. The exact mechanism of disease is uncertain. This gene-disease association is also supported by known biochemical function, expression, functional alteration in patient cells, and animal models (PMIDs: 27977873, 25613900, 27693233). In summary, there is limited 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 U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on March 24, 2021 (SOP Version 7).

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012238

Submitter: PanelApp Australia

mitochondrial DNA depletion syndrome 12B (cardiomyopathic type), autosomal recessiveDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014175

Submitter: ClinGen

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: G2P

mitochondrial DNA depletion syndrome 12B (cardiomyopathic type), autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014175

Submitter: PanelApp Australia

progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0012238

Submitter: Ambry Genetics

Fontaine progeroid syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012853

Submitter: G2P

mitochondrial DNA depletion syndrome 12B (cardiomyopathic type), autosomal recessiveMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014175

Submitter: Ambry Genetics

mitochondrial DNA depletion syndrome 12A (cardiomyopathic type), autosomal dominantMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014959

Submitter: Ambry Genetics

autosomal dominant progressive external ophthalmoplegiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008003

Submitter: Orphanet

Clinical Genomic Database (CGD)

Manifestation: Audiologic/Otolaryngologic; Cardiovascular; Endocrine; Musculoskeletal; Neurologic

Intervention: Cardiovascular; Endocrine

Rationale: 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

Comments: Cardiomyopathy has only been described in an individual with a homozygous variant

Refs: 10926541; 11756592; 1756613; 12112115; 12210792; 16155110; 27693233

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC25A4 variants in ClinVar

19 Conditions Cataloged

not providedTotal: 186

not specifiedTotal: 36

Inborn genetic diseasesTotal: 26

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2Total: 20

Mitochondrial DNA depletion syndrome 12B (cardiomyopathic type), autosomal recessiveTotal: 19

SLC25A4-related disorderTotal: 16

Mitochondrial DNA depletion syndrome 12A (cardiomyopathic type), autosomal dominantTotal: 12

Mitochondrial diseaseTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001151.4. 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			1 clinvar	67 clinvar	2 clinvar	70
missense	6 clinvar	9 clinvar	114 clinvar	3 clinvar		132
nonsense	1 clinvar					1
start loss						0
frameshift	5 clinvar	4 clinvar	3 clinvar			12
splice donor/acceptor (+/-2bp)	1 clinvar	1 clinvar				2
Total	13	14	118	70	2	217

Highest pathogenic variant AF is 0.000013630208

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 41 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001151.4	RefSeq	NP_001142.2	4	MANE Select
ENST00000281456.11	Ensembl	ENSP00000281456.5	4	MANE Select
ENST00000491736.1	Ensembl	ENSP00000476711.1	3	Standard
ENST00000889779.1	Ensembl	ENSP00000559838.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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)

Biological Process

mitochondrial genome maintenance
generation of precursor metabolites and energy
apoptotic mitochondrial changes
adenine transport
ADP transport

Molecular Function

ATP:ADP antiporter activity
protein binding
adenine transmembrane transporter activity

Cellular Component

mitochondrion
mitochondrial inner membrane
integral component of plasma membrane
integral component of mitochondrial membrane
myelin sheath

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000281456
Coding exons: 4
Length: 7142
Individuals with no LoFs: 125741
Homozygous LoFs: 0
Heterozygous LoFs: 7
Defined: 125748
p: 0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.87	105	175	0.601	0.0000103	1956
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000055	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000044	0.000044	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec: 0.413

Intolerance Scores

LoFtool: 0.172
RVIS EVS: 0.06
RVIS percentile EVS: 58.26

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.920

Gene Damage Prediction

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