IBA57

Chr 1AR

iron-sulfur cluster assembly factor IBA57

Also known as: C1orf69, MMDS3, SPG74

NCBI Gene: 200205 ENSG00000181873 UniProt: Q5T440 OMIM: 615316

The protein functions in the late stages of mitochondrial iron-sulfur cluster assembly, specifically in the biosynthesis of 4Fe-4S proteins essential for mitochondrial respiratory chain complexes. Mutations cause autosomal recessive spastic paraplegia-74 and multiple mitochondrial dysfunctions syndrome-3 through impaired iron-sulfur cluster biogenesis, leading to mitochondrial respiratory chain dysfunction.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 0.962 OMIM phenotypes

Clinical Summary— IBA57

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Gene-Disease Validity (ClinGen)

mitochondrial disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

40 unique Pathogenic / Likely Pathogenic· 163 VUS of 344 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.96LOEUF

pLI 0.008

Z-score 1.67

OE 0.46 (0.24–0.96)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.57Z-score

OE missense 1.11 (1.00–1.25)

219 obs / 196.4 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.46 (0.24–0.96)

0≤0.351.4

Missense OE?1.11 (1.00–1.25)

0≤0.61.4

Synonymous OE?1.24

0≤1.21.6

LoF obs/exp: 5 / 11.0Missense obs/exp: 219 / 196.4Syn Z: -1.83

This gene — mechanism propensity

0.6841th %ile

GOF

0.5366th %ile

LOF

0.3941th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

344 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic22

Likely Pathogenic18

VUS163

Likely Benign111

Benign8

Conflicting9

Pathogenic

Likely Pathogenic

163

VUS

111

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	16	5	0	1	22
Likely Pathogenic	13	5	0	0	18
VUS	4	151	6	2	163
Likely Benign	0	5	20	86	111
Benign	0	2	5	1	8
Conflicting	—				9
Total	33	168	31	90	331

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

35 pathogenic / likely-pathogenic (of 45) ClinVar copy-number / structural variants overlap IBA57 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →