AFG2A

protein-coding

AFG2 AAA ATPase homolog A, the group of AAA ATPases

Gene summary

This gene encodes a member of the ATPase associated with diverse activities family, whose members are defined by a highly conserved ATPase domain. Members of this family participate in diverse cellular processes that include membrane fusion, DNA replication, microtubule severing, and protein degradation. The protein encoded by this gene has a putative mitochondrial targeting sequence and has been proposed to function in maintenance of mitochondrial function and integrity during mouse spermatogenesis. Allelic variants in this gene have been associated with epilepsy, hearing loss, and cognitive disability syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

Previous symbols:

SPATA5

MANE transcript

NM_145207.3

Inheritance

ClinVar variants

P:108U:367B:218

Top phenotype

Neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities

gnomAD constraint

pLI —, LoF o/e 0.81

Max pathogenic AF

—

Genomic locus

chr4:122,923,070-123,319,433

External References & Databases

Ensembl (ENSG00000145375)

Transcript & Mutation Effects

hg38 • Region Span ~396.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

syndromic complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0800439

Submitter: ClinGen

The *AFG2A* gene is located on chromosome 4 at 4q28.1 and encodes a member of the ATPase associated with diverse activities (AAA) protein family. *AFG2A* was first reported in connection with autosomal recessive syndromic complex neurodevelopmental disorder in 2015 (Tanaka et al., 2015 PMID: 26299366). Affected individuals are characterized by microcephaly, global developmental delay, intellectual disability, abnormal muscle tone, and sensorineural hearing impairment. Additional variable manifestations include epilepsy, cortical visual impairment, gastrointestinal disturbances, growth restriction, scoliosis, as well as immunodeficiency and thrombocytopenia. Brain imaging may show cerebral atrophy, thin corpus callosum, and hypomyelination. Twenty variants (11 missense, 5 nonsense, 2 frameshift, 1 canonical splice site, 1 deletion) reported in 18 probands across 2 publications are included in this curation (PMIDs: 29343804, 26299366). The mechanism of disease is reported to be loss-of-function. The maximum points for genetic evidence (12pts) was reached, however, additional cases are available in the literature (PMIDs: 34949788, 27246907). This gene-disease relationship is also supported by experimental evidence including functional alteration in non-patient cells and biochemical function (PMIDs: 29343804, 38554706). In summary, there is definitive evidence supporting the relationship between *AFG2A* and autosomal recessive syndromic complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date July 23rd, 2024 (SOP Version 10).

microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014698

Submitter: Labcorp Genetics (formerly Invitae)

microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014698

Submitter: Orphanet

microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014698

Submitter: G2P

microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014698

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with hearing loss, seizures, and brain abnormalitiesAR

Manifestation: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Hematologic; Neurologic

Intervention: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic

Rationale: Although details are unclear, multiple individuals have been described as having immunodefiency, and awareness may allow prompt and aggressive treatment of infections; Among other findings, the condition can include sensorineural hearing loss, and some patients may benefit from early recognition and management of hearing loss

Refs: 21822266; 26299366

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AFG2A variants in ClinVar

12 Conditions Cataloged

Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndromeTotal: 757

not providedTotal: 160

Inborn genetic diseasesTotal: 91

not specifiedTotal: 20

AFG2A-related disorderTotal: 12

Syndromic complex neurodevelopmental disorderTotal: 3

Neurodevelopmental disorderTotal: 2

SPATA5-related neurodevelopmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_145207.3. 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			4 clinvar	196 clinvar	1 clinvar	201
missense	4 clinvar	25 clinvar	359 clinvar	17 clinvar	4 clinvar	409
nonsense	22 clinvar	9 clinvar	1 clinvar			32
start loss		2 clinvar	2 clinvar			4
frameshift	26 clinvar	6 clinvar	1 clinvar			33
splice donor/acceptor (+/-2bp)	2 clinvar	12 clinvar				14
Total	54	54	367	213	5	693

Highest pathogenic variant AF is 0.00019176847

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 40 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_145207.3	RefSeq	NP_660208.2	16	MANE Select
ENST00000274008.5	Ensembl	ENSP00000274008.3	16	MANE Select
NM_001317799.2	RefSeq	NP_001304728.1	11	Standard
NM_001345856.2	RefSeq	NP_001332785.1	16	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ribosome biogenesis in eukaryotes - Homo sapiens (human)

Biological Process

spermatogenesis
brain development
cell differentiation

Molecular Function

ATP binding
ATPase activity

Cellular Component

cytoplasm
mitochondrion

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000274008
Coding exons: 16
Length: 396377
Individuals with no LoFs: 125625
Homozygous LoFs: 0
Heterozygous LoFs: 123
Defined: 125748
p: 0.000489

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.460	446	474	0.941	0.0000232	5803
Missense (PolyPhen)		151	182.91	0.82556		2171
Synonymous	0.601	163	173	0.942	0.00000844	1790
Loss of Function	1.14	34	42.0	0.810	0.00000250	504

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00050	0.00049	rare
Finnish	0.00028	0.00028	rare
European (Non-Finnish)	0.00071	0.00070	rare
South Asian	0.00033	0.00033	rare
Other	0.00066	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: ATP-dependent chaperone which uses the energy provided by ATP hydrolysis to generate mechanical force to disassemble protein complexes. May be involved in morphological and functional mitochondrial transformations during spermatogenesis. {ECO:0000250|UniProtKB:P32794, ECO:0000250|UniProtKB:Q3UMC0}.;
Disease: DISEASE: Epilepsy, hearing loss, and mental retardation syndrome (EHLMRS) [MIM:616577]: An autosomal recessive disorder characterized by intellectual disability, intractable epilepsy, microcephaly, abnormal muscle tone, and sensorineural hearing loss. {ECO:0000269|PubMed:26299366}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.108

Intolerance Scores

LoFtool: 0.181
RVIS EVS: -0.22
RVIS percentile EVS: 37.66

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: N
Indispensability score: 0.385

Gene Damage Prediction

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