AIFM1

apoptosis inducing factor mitochondria associated 1

Basic information

Region (hg38): X:130124665-130165879

Previous symbols: [ "PDCD8", "NAMSD", "AUNX1" ]

Links

ENSG00000156709 ∙ NCBI:9131 ∙ OMIM:300169 ∙ HGNC:8768 ∙ Uniprot:O95831 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• X-linked hereditary sensory and autonomic neuropathy with hearing loss (Strong), mode of inheritance: XL
• severe X-linked mitochondrial encephalomyopathy (Strong), mode of inheritance: XLR
• spondyloepimetaphyseal dysplasia, Bieganski type (Supportive), mode of inheritance: XL
• Charcot-Marie-Tooth disease X-linked recessive 4 (Supportive), mode of inheritance: XL
• X-linked hereditary sensory and autonomic neuropathy with hearing loss (Supportive), mode of inheritance: XL
• severe X-linked mitochondrial encephalomyopathy (Supportive), mode of inheritance: XL
• severe X-linked mitochondrial encephalomyopathy (Strong), mode of inheritance: XL
• X-linked hereditary sensory and autonomic neuropathy with hearing loss (Strong), mode of inheritance: XL
• severe X-linked mitochondrial encephalomyopathy (Strong), mode of inheritance: XL
• spondyloepimetaphyseal dysplasia, Bieganski type (Strong), mode of inheritance: XL
• Charcot-Marie-Tooth disease X-linked recessive 4 (Strong), mode of inheritance: XL
• X-linked hereditary sensory and autonomic neuropathy with hearing loss (Definitive), mode of inheritance: XL
• Leigh syndrome (Moderate), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Deafness, X-linked 5	XL	Audiologic/Otolaryngologic	Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development	Audiologic/Otolaryngologic; Biochemical; Cardiovascular; Musculoskeletal; Neurologic	16816020; 20362274; 22019070; 23217327; 25986071; 27102849; 28842795

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the AIFM1 gene.

• not provided (143 variants)
• Combined oxidative phosphorylation deficiency;Charcot-Marie-Tooth Neuropathy X (134 variants)
• Charcot-Marie-Tooth Neuropathy X;Combined oxidative phosphorylation deficiency (113 variants)
• Inborn genetic diseases (53 variants)
• Severe X-linked mitochondrial encephalomyopathy (36 variants)
• not specified (23 variants)
• Charcot-Marie-Tooth disease (19 variants)
• Deafness, X-linked 5 (11 variants)
• Spondyloepimetaphyseal dysplasia, Bieganski type (8 variants)
• Charcot-Marie-Tooth disease X-linked recessive 4 (6 variants)
• Auditory neuropathy (4 variants)
• AIFM1-related condition (4 variants)
• Charcot-Marie-Tooth disease X-linked recessive 4;Deafness, X-linked 5;Severe X-linked mitochondrial encephalomyopathy;Spondyloepimetaphyseal dysplasia, Bieganski type (4 variants)
• Tip-toe gait (3 variants)
• Distal muscle weakness;Foot dorsiflexor weakness;Pes planus;Sensorineural hearing loss disorder (1 variants)
• Severe X-linked mitochondrial encephalomyopathy;Charcot-Marie-Tooth disease X-linked recessive 4;Deafness, X-linked 5;Spondyloepimetaphyseal dysplasia, Bieganski type (1 variants)
• Charcot-Marie-Tooth disease X-linked recessive 4;Severe X-linked mitochondrial encephalomyopathy (1 variants)
• Leukodystrophy (1 variants)
• AIFM1-related hypomyelination with spondylometaphyseal dysplasia (1 variants)
• Charcot-Marie-Tooth disease X-linked recessive 4;Deafness, X-linked 5;Severe X-linked mitochondrial encephalomyopathy (1 variants)
• Intellectual disability (1 variants)
• Charcot-Marie-Tooth disease X-linked recessive 4;Deafness, X-linked 5;Spondyloepimetaphyseal dysplasia, Bieganski type;Severe X-linked mitochondrial encephalomyopathy (1 variants)
• Ear malformation (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the AIFM1 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	64	3	68
missense		16	136	14	2	168
nonsense						0
start loss		1	1			2
frameshift						0
inframe indel			4			4
splice donor/acceptor (+/-2bp)						0
splice region			12	9	1	22
non coding			8	66	16	90
Total	0	17	150	144	21

Variants in AIFM1

This is a list of pathogenic ClinVar variants found in the AIFM1 region.

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

Position	Type	Phenotype	Significance	ClinVar
X-130129397-T-C			Likely benign (Sep 29, 2018)
X-130129508-G-A		Severe X-linked mitochondrial encephalomyopathy	Uncertain significance (Jan 13, 2018)
X-130129537-G-T		Charcot-Marie-Tooth disease	Likely benign (-)
X-130129566-A-G		not specified • Combined oxidative phosphorylation deficiency;Charcot-Marie-Tooth Neuropathy X • Severe X-linked mitochondrial encephalomyopathy • Inborn genetic diseases • Deafness, X-linked 5;Severe X-linked mitochondrial encephalomyopathy;Charcot-Marie-Tooth disease X-linked recessive 4;Spondyloepimetaphyseal dysplasia, Bieganski type • Charcot-Marie-Tooth disease	Benign/Likely benign (Jan 31, 2024)
X-130129578-T-C		Charcot-Marie-Tooth Neuropathy X;Combined oxidative phosphorylation deficiency	Likely benign (Sep 25, 2021)
X-130129579-A-T		Combined oxidative phosphorylation deficiency;Charcot-Marie-Tooth Neuropathy X	Uncertain significance (Nov 22, 2022)
X-130129594-T-C		Charcot-Marie-Tooth Neuropathy X;Combined oxidative phosphorylation deficiency	Uncertain significance (Mar 22, 2020)
X-130129605-A-G		not specified • Inborn genetic diseases • Combined oxidative phosphorylation deficiency;Charcot-Marie-Tooth Neuropathy X	Likely benign (Oct 21, 2022)
X-130129616-C-T		Combined oxidative phosphorylation deficiency;Charcot-Marie-Tooth Neuropathy X	Uncertain significance (Apr 26, 2023)
X-130129617-G-A		Charcot-Marie-Tooth disease	Likely benign (-)
X-130129618-T-G		Charcot-Marie-Tooth Neuropathy X;Combined oxidative phosphorylation deficiency	Uncertain significance (Sep 01, 2022)
X-130129620-C-T		Charcot-Marie-Tooth Neuropathy X;Combined oxidative phosphorylation deficiency	Likely benign (Jul 31, 2022)
X-130129626-G-C		Deafness, X-linked 5	Likely pathogenic (-)
X-130129636-A-G		Charcot-Marie-Tooth Neuropathy X;Combined oxidative phosphorylation deficiency	Likely benign (Apr 18, 2023)
X-130129637-G-A			Likely benign (May 16, 2018)
X-130129639-G-A		Combined oxidative phosphorylation deficiency;Charcot-Marie-Tooth Neuropathy X	Likely benign (Feb 18, 2023)
X-130129640-A-G		Charcot-Marie-Tooth Neuropathy X;Combined oxidative phosphorylation deficiency	Likely benign (Mar 28, 2022)
X-130129640-AGAGT-A		Charcot-Marie-Tooth Neuropathy X;Combined oxidative phosphorylation deficiency	Likely benign (Feb 24, 2022)
X-130129641-G-A		Combined oxidative phosphorylation deficiency;Charcot-Marie-Tooth Neuropathy X	Likely benign (Jun 30, 2023)
X-130129642-A-T		Charcot-Marie-Tooth Neuropathy X;Combined oxidative phosphorylation deficiency	Likely benign (Jan 14, 2023)
X-130129824-C-T			Likely benign (Aug 03, 2018)
X-130129958-A-G		Spondyloepimetaphyseal dysplasia, Bieganski type • Combined oxidative phosphorylation deficiency;Charcot-Marie-Tooth Neuropathy X	Conflicting classifications of pathogenicity (Nov 28, 2023)
X-130129959-C-T		Combined oxidative phosphorylation deficiency;Charcot-Marie-Tooth Neuropathy X	Likely benign (Aug 04, 2023)
X-130129963-C-A		Combined oxidative phosphorylation deficiency;Charcot-Marie-Tooth Neuropathy X	Likely benign (Jun 30, 2023)
X-130129965-C-A		Combined oxidative phosphorylation deficiency;Charcot-Marie-Tooth Neuropathy X	Uncertain significance (Aug 24, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
AIFM1	protein_coding	protein_coding	ENST00000287295	16	36525

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.998	0.00205	125711	0	2	125713	0.00000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.49	130	238	0.545	0.0000184	3955
Missense in Polyphen		14	67.99	0.20591		1088
Synonymous	0.569	86	93.0	0.925	0.00000774	1231
Loss of Function	4.45	2	26.9	0.0743	0.00000222	408

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	0.00	0.00
European (Non-Finnish)	0.0000122	0.00000879
Middle Eastern	0.00	0.00
South Asian	0.0000524	0.0000327
Other	0.00	0.00

dbNSFP

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.
• Pathway: Necroptosis - Homo sapiens (human);Apoptosis - Homo sapiens (human);Apoptosis Modulation and Signaling;Nanomaterial induced apoptosis;Apoptosis Modulation by HSP70;RAGE;role of mitochondria in apoptotic signaling;opposing roles of aif in apoptosis and cell survival;ceramide signaling pathway;Ceramide signaling pathway (Consensus)

Recessive Scores

• pRec: 0.380

Intolerance Scores

• loftool: 0.0837
• rvis_EVS: -0.27
• rvis_percentile_EVS: 34.6

Haploinsufficiency Scores

• pHI: 0.325
• hipred: Y
• hipred_score: 0.729
• ghis: 0.547

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.773

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Aifm1
• 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; cellular phenotype; homeostasis/metabolism phenotype; muscle phenotype; vision/eye 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); 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); embryo phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); 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)

Gene ontology

• Biological process: response to ischemia;apoptotic process;activation of cysteine-type endopeptidase activity involved in apoptotic process;chromosome condensation;positive regulation of apoptotic process;positive regulation of neuron apoptotic process;neuron apoptotic process;oxidation-reduction process;intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress;cellular response to hydrogen peroxide;cellular response to estradiol stimulus;cellular response to nitric oxide;cellular response to oxygen-glucose deprivation;response to L-glutamate;regulation of apoptotic DNA fragmentation;cellular response to aldosterone
• Cellular component: nucleus;mitochondrion;mitochondrial inner membrane;mitochondrial intermembrane space;cytosol;perinuclear region of cytoplasm
• Molecular function: DNA binding;protein binding;NAD(P)H oxidase activity;oxidoreductase activity, acting on NAD(P)H;protein dimerization activity;FAD binding