IBA57

protein-coding

iron-sulfur cluster assembly factor IBA57, the group of Mitochondrial iron-sulfur assembly components

Gene summary

The protein encoded by this gene localizes to the mitochondrion and is part of the iron-sulfur cluster assembly pathway. The encoded protein functions late in the biosynthesis of mitochondrial 4Fe-4S proteins. Defects in this gene have been associated with autosomal recessive spastic paraplegia-74 and with multiple mitochondrial dysfunctions syndrome-3. Two transcript variants encoding different isoforms have been found for this gene. The smaller isoform is not likely to be localized to the mitochondrion since it lacks the amino-terminal transit peptide. [provided by RefSeq, Jul 2015]

Previous symbols:

C1orf69

MANE transcript

NM_001010867.4

Inheritance

ClinVar variants

P:45U:166B:97

Top phenotype

Multiple mitochondrial dysfunctions syndrome 3; Spastic paraplegia 74, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.46

Max pathogenic AF

—

Genomic locus

chr1:228,165,804-228,182,257

External References & Databases

Ensembl (ENSG00000181873)

Transcript & Mutation Effects

hg38 • Region Span ~16.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

multiple mitochondrial dysfunctions syndrome 3SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014132

Submitter: Orphanet

hereditary spastic paraplegia 74SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014644

Submitter: Orphanet

multiple mitochondrial dysfunctions syndrome 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014132

Submitter: Genomics England PanelApp

multiple mitochondrial dysfunctions syndrome 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014132

Submitter: PanelApp Australia

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *IBA57* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of July 11, 2023. *IBA57* encodes an iron-sulfur cluster assembly protein that acts late in the biosynthetic pathway of mitochondrial 4Fe-4S proteins. *IBA57* was first reported in relation to autosomal recessive primary mitochondrial disease in 2013 (PMID: 23462291), in a neonate with intrauterine growth restriction, brain malformations detected in utero, hypotonia, microcephaly, and hyperglycinemia who died perinatally. While various names have been given to the constellation of features seen in those with *IBA57*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *IBA57* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included six unique variants (three missense, two nonsense, and one predicted missense variant resulting in splicing abnormalities), in five probands across four publications (PMIDs: 23462291, 25971455, 25609768, 28913435). Compelling familial segregation data was also included in scoring (PMID: 25609768). There are at least 50 cases reported in the literature through 2022 (PMID: 36360281). Two general clinical phenotypes have been reported. One is an infantile onset, sometimes fatal, microcephaly and cavitating leukodystrophy with or without other brain malformations with metabolic acidosis and hyperglycinemia. The other is childhood/adolescent onset spastic paraplegia with or without optic atrophy. Notably, this second phenotype is reported in relation to a variant impacting splicing. Affected individuals show reduction in activities and amounts of lipoate containing enzymes (PMIDs: 23462291, 25971455, 25609768, 28913435). This gene-disease association is also supported by functional implication given protein interaction with other proteins of the Fe-S cluster biosynthesis and assembly machinery and the lipoylation pathway, as well as functional alteration in patient cells (PMIDs: 33007329, 27785568). In summary, there is definitive evidence to support the relationship between *IBA57* and primary mitochondrial disease. This has been repeatedly demonstrated and upheld over time, and no convincing evidence has emerged that contradicts this gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on July 11, 2023 (SOP Version 9).

hereditary spastic paraplegia 74LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014644

Submitter: Labcorp Genetics (formerly Invitae)

multiple mitochondrial dysfunctions syndrome 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014132

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Multiple mitochondrial dysfunctions syndrome 3; Spastic paraplegia 74, autosomal recessiveAR

Manifestation: Biochemical; Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 23462291; 25609768

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IBA57 variants in ClinVar

9 Conditions Cataloged

Multiple mitochondrial dysfunctions syndrome 3Total: 228

Hereditary spastic paraplegia 74Total: 210

not providedTotal: 95

Inborn genetic diseasesTotal: 74

not specifiedTotal: 26

IBA57-related disorderTotal: 16

Possible mitochondrial disorder - nuclear genesTotal: 1

MicrocephalyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001010867.4. 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		4 clinvar	89 clinvar	1 clinvar	95
missense	5 clinvar	7 clinvar	156 clinvar	7 clinvar		175
nonsense	9 clinvar	2 clinvar				11
start loss						0
frameshift	8 clinvar	9 clinvar	4 clinvar			21
splice donor/acceptor (+/-2bp)		4 clinvar	2 clinvar			6
Total	23	22	166	96	1	308

Highest pathogenic variant AF is 0.00006045107

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 6 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001010867.4	RefSeq	NP_001010867.1	3	MANE Select
ENST00000366711.4	Ensembl	ENSP00000355672.3	3	MANE Select
NM_001310327.2	RefSeq	NP_001297256.1	2	Standard
ENST00000949083.1	Ensembl	ENSP00000619142.1	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
iba57	Danio rerio	Structure: nucleate erythrocyte Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

iba57

Danio rerio

Structure: nucleate erythrocyte

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

heme biosynthetic process
iron-sulfur cluster assembly

Molecular Function

RNA binding
transferase activity

Cellular Component

mitochondrion
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000366711
Coding exons: 3
Length: 16443
Individuals with no LoFs: 125453
Homozygous LoFs: 0
Heterozygous LoFs: 13
Defined: 125466
p: 0.0000518

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.572	219	196	1.11	0.0000124	2170
Missense (PolyPhen)		62	65.768	0.94271		712
Synonymous	-1.83	115	92.6	1.24	0.00000587	827
Loss of Function	1.67	5	11.0	0.455	8.00e-7	97

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00017	0.00016	rare
Finnish	0.000058	0.000046	rare
European (Non-Finnish)	0.000048	0.000044	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the maturation of mitochondrial 4Fe-4S proteins functioning late in the iron-sulfur cluster assembly pathway. {ECO:0000269|PubMed:23462291}.;
Disease: DISEASE: Spastic paraplegia 74, autosomal recessive (SPG74) [MIM:616451]: A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPG74 is characterized by a combination of spastic paraplegia, optic atrophy, and peripheral neuropathy with childhood-onset and slow progression into late adulthood. {ECO:0000269|PubMed:25609768}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0980

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

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