GeneBe

AIFM1

protein-coding

apoptosis inducing factor mitochondria associated 1

Gene summary

This gene encodes a flavoprotein essential for nuclear disassembly in apoptotic cells, and it is found in the mitochondrial intermembrane space in healthy cells. Induction of apoptosis results in the translocation of this protein to the nucleus where it affects chromosome condensation and fragmentation. In addition, this gene product induces mitochondria to release the apoptogenic proteins cytochrome c and caspase-9. Mutations in this gene cause combined oxidative phosphorylation deficiency 6 (COXPD6), a severe mitochondrial encephalomyopathy, as well as Cowchock syndrome, also known as X-linked recessive Charcot-Marie-Tooth disease-4 (CMTX-4), a disorder resulting in neuropathy, and axonal and motor-sensory defects with deafness and cognitive disability. Alternative splicing results in multiple transcript variants. A related pseudogene has been identified on chromosome 10. [provided by RefSeq, Aug 2015]

Previous symbols:
  • PDCD8
  • NAMSD
  • AUNX1

MANE transcript

NM_004208.4

Inheritance

XL

ClinVar variants

P:53U:381B:147

Top phenotype

Deafness, X-linked 5

gnomAD constraint

pLI —, LoF o/e 0.07

Max pathogenic AF

—

Genomic locus

chrX:130,124,666-130,165,879

External References & Databases

Ensembl (ENSG00000156709)NCBI Gene (9131)OMIM (300169)HGNC:8768GenCCUniProt (O95831)AlphaFoldClinVar (AIFM1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~41.2 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Charcot-Marie-Tooth disease X-linked recessive 4STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010689

Submitter: PanelApp Australia

X-linked hereditary sensory and autonomic neuropathy with hearing lossDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010378

Submitter: ClinGen

AIFM1was first reported in relation to X-linked hereditary sensory and autonomic neuropathy with deafness in 2006 (Wang et al., PMID:16816020). Using case-level data, this gene has been associated with X-linked disease that presents with a spectrum of auditory and sensory neuropathy phenotypes using the ClinGen Clinical Validity Framework. At least 24 variants (missense, splice site, in-frame deletion) that have been reported in 36 probands in 10 publications (PMIDs:25986071, 20362274, 23217327, 28888069, 28975462, 28842795, 27102849, 38456936, 36479253, 31523922) are included in this curation. Variants in this gene segregated with disease in >25 additional family members. This gene-disease association is also supported by functional assays, expression studies, and a mouse model (PMIDs: 23217327, 20362274, 25986071, 38449065) showing that AIFM1 plays a role in apoptosis and impairment of the auditory pathway in patients. In summary, AIFM1 is definitively associated with X-linked hereditary sensory and autonomic neuropathy with deafness. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was originally approved by the ClinGen Hearing Loss Working Group on 7/9/2018. It was reevaluated on 8/26/2025 (SOP Version 11). As a result of this reevaluation, the classification did not change.

severe X-linked mitochondrial encephalomyopathySTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010437

Submitter: PanelApp Australia

spondyloepimetaphyseal dysplasia, Bieganski typeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010275

Submitter: Labcorp Genetics (formerly Invitae)

severe X-linked mitochondrial encephalomyopathySTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010437

Submitter: G2P

Charcot-Marie-Tooth disease X-linked recessive 4STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010689

Submitter: Labcorp Genetics (formerly Invitae)

spondyloepimetaphyseal dysplasia, Bieganski typeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010275

Submitter: PanelApp Australia

Leigh syndromeMODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between AIFM1 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of August 17, 2020. The AIFM1 gene encodes apoptosis-inducing factor, mitochondria-associated, 1 which is an FAD-dependent oxidoreductase with important roles in oxidative phosphorylation, apoptosis, and redox control. The AIFM1 gene was first reported in relation to X-linked Leigh syndrome spectrum in 2010 (PMID: 20362274). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included four unique variants identified in four cases from four publications (PMIDs: 20362274, 22019070, 25934856, 28299359). No segregation data were available. AIFM1 variants have also been reported to be associated with X-linked Charcot-Marie-Tooth disease-4 (CMTX-4, also known as Cowchock syndrome). Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by expression, functional alteration in patient cells, functional alteration in non-patient cells, and animal models (PMIDs: 18791645, 20362274, 15526035, 29780003, 29531799, 18309327). 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 U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on August 17, 2020 (SOP Version 7).

X-linked hereditary sensory and autonomic neuropathy with hearing lossSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010378

Submitter: Labcorp Genetics (formerly Invitae)

Charcot-Marie-Tooth disease X-linked recessive 4SUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010689

Submitter: Orphanet

X-linked hereditary sensory and autonomic neuropathy with hearing lossSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010378

Submitter: Orphanet

severe X-linked mitochondrial encephalomyopathySTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010437

Submitter: Labcorp Genetics (formerly Invitae)

spondyloepimetaphyseal dysplasia, Bieganski typeSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010275

Submitter: Orphanet

severe X-linked mitochondrial encephalomyopathySUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010437

Submitter: Orphanet

X-linked hereditary sensory and autonomic neuropathy with hearing lossSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010378

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Deafness, X-linked 5XL

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

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 16816020; 20362274; 22019070; 23217327; 25986071; 27102849; 28842795Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AIFM1 variants in ClinVar

27 Conditions Cataloged
Charcot-Marie-Tooth Neuropathy XTotal: 386
Combined oxidative phosphorylation deficiencyTotal: 386
not providedTotal: 183
not specifiedTotal: 68
Inborn genetic diseasesTotal: 66
AIFM1-related disorderTotal: 58
Severe X-linked mitochondrial encephalomyopathyTotal: 46
Deafness, X-linked 5Total: 36

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004208.4. 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.

EffectPLPVUSLBBSum
synonymous
43
clinvar
101
clinvar
5
clinvar
 149
missense
8
clinvar
45
clinvar
285
clinvar
39
clinvar
2
clinvar
 379
nonsense
7
clinvar
 7
start loss
0
frameshift
0
splice donor/acceptor (+/-2bp)
46
clinvar
 46
Total8453811407581

Highest pathogenic variant AF is 0.000006374061

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 60 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_004208.4RefSeqNP_004199.116MANE Select
ENST00000287295.8EnsemblENSP00000287295.316MANE Select
NM_001130846.4RefSeqNP_001124318.27Standard
NM_001130847.4RefSeqNP_001124319.110Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Necroptosis - Homo sapiens (human)
  • Apoptosis - Homo sapiens (human)
  • Apoptosis Modulation and Signaling
  • Nanomaterial induced apoptosis
  • Apoptosis Modulation by HSP70

Biological Process

  • response to ischemia
  • apoptotic process
  • activation of cysteine-type endopeptidase activity involved in apoptotic process
  • chromosome condensation
  • positive regulation of apoptotic process

Molecular Function

  • DNA binding
  • protein binding
  • NAD(P)H oxidase activity
  • oxidoreductase activity, acting on NAD(P)H
  • protein dimerization activity

Cellular Component

  • nucleus
  • mitochondrion
  • mitochondrial inner membrane
  • mitochondrial intermembrane space
  • cytosol

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000287295
Coding exons
16
Length
36525
Individuals with no LoFs
125711
Homozygous LoFs
0
Heterozygous LoFs
2
Defined
125713
p
0.00000795
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.491302380.5450.00001843955
Missense (PolyPhen)1467.990.205911088
Synonymous0.5698693.00.9250.000007741231
Loss of Function4.45226.90.07430.00000222408

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000120.0000088rare
South Asian0.0000520.000033rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Functions both as NADH oxidoreductase and as regulator of apoptosis. In response to apoptotic stimuli, it is released from the mitochondrion intermembrane space into the cytosol and to the nucleus, where it functions as a proapoptotic factor in a caspase-independent pathway. In contrast, functions as an antiapoptotic factor in normal mitochondria via its NADH oxidoreductase activity. The soluble form (AIFsol) found in the nucleus induces 'parthanatos' i.e. caspase-independent fragmentation of chromosomal DNA. Interacts with EIF3G,and thereby inhibits the EIF3 machinery and protein synthesis, and activates casapse-7 to amplify apoptosis. Plays a critical role in caspase- independent, pyknotic cell death in hydrogen peroxide-exposed cells. Binds to DNA in a sequence-independent manner. {ECO:0000269|PubMed:17094969, ECO:0000269|PubMed:19418225, ECO:0000269|PubMed:20362274, ECO:0000269|PubMed:23217327}.;
Disease
DISEASE: Combined oxidative phosphorylation deficiency 6 (COXPD6) [MIM:300816]: A mitochondrial disease resulting in a neurodegenerative disorder characterized by psychomotor delay, hypotonia, areflexia, muscle weakness and wasting. Some patients manifest prenatal ventriculomegaly and severe postnatal encephalomyopathy. {ECO:0000269|PubMed:20362274, ECO:0000269|PubMed:22019070}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cowchock syndrome (COWCK) [MIM:310490]: An X-linked recessive neuromuscular disorder characterized by early childhood onset of a slowly progressive axonal sensorimotor neuropathy associated in some patients with sensorineural deafness and cognitive impairment. {ECO:0000269|PubMed:23217327}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Deafness, X-linked, 5 (DFNX5) [MIM:300614]: A form of hearing loss characterized by absent or severely abnormal auditory brainstem response, abnormal middle ear reflexes, abnormal speech discrimination, loss of outer hair cell function, and cochlear nerve hypoplasia. DFNX5 patients manifest auditory neuropathy with childhood onset, associated with distal sensory impairment affecting the peripheral nervous system. {ECO:0000269|PubMed:25986071}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.380

Intolerance Scores

LoFtool
0.0837
RVIS EVS
-0.27
RVIS percentile EVS
34.6

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
E
Essential (gene trap)
E
Indispensability pred.
E
Indispensability score
0.773

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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