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…

Primary Disease Associations & Inheritance

?Spastic paraplegia 74, autosomal recessiveMIM #616451

Multiple mitochondrial dysfunctions syndrome 3MIM #615330

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · mitochondrial disease · AR · ClinGen 2023

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.96

LOEUF

Mechanism· predicted

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

Background carrier burden — how many people carry a rare variant somewhere in IBA57?

gnomAD v4 · ~730k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 98

647 rare PASS variants

Rare truncating (LoF)

1 in 1,400

92 rare PASS variants

Rare synonymous (reference)

1 in 140

328 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for IBA57. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 140	1 in 1,400
South Asian	~43k	1 in 120	1 in 3,400
Remaining (unassigned)	~30k	1 in 87	1 in 1,700
European (Finnish)	~26k	1 in 340	1 in 1,900
Admixed American	~22k	1 in 84	1 in 1,800
African / African American	~21k	1 in 77	1 in 720
East Asian	~20k	1 in 100	1 in 900
Ashkenazi Jewish	~13k	1 in 530	none seen
Middle Eastern	~2,884	1 in 110	1 in 560

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 2 of 3 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 3.? see exons ↓