BOLA3

Chr 2AR

bolA family member 3

Also known as: MMDS2

NCBI Gene: 388962 ENSG00000163170 UniProt: Q53S33 OMIM: 613183

The protein is essential for iron-sulfur cluster production required for maturation of lipoate-containing 2-oxoacid dehydrogenases and assembly of mitochondrial respiratory chain complexes. Mutations cause multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemia, inherited in an autosomal recessive pattern. The pathogenic mechanism involves dominant-negative effects disrupting normal mitochondrial function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a protein that plays an essential role in the production of iron-sulfur (Fe-S) clusters for the normal maturation of lipoate-containing 2-oxoacid dehydrogenases, and for the assembly of the mitochondrial respiratory chain complexes. Mutation in this gene has been associated with multiple mitochondrial dysfunctions syndrome-2. Two alternatively spliced transcript variants encoding different isoforms with distinct subcellular localization have been reported for this gene (PMID:21944046). [provided by RefSeq, Dec 2011]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemiaMIM #614299

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · mitochondrial disease · AR · ClinGen 2023

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.06

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — BOLA3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.06LOEUF

pLI 0.149

Z-score 1.50

OE 0.34 (0.14–1.06)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.55Z-score

OE missense 0.80 (0.64–1.02)

48 obs / 59.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.34 (0.14–1.06)

0≤0.351.4

Missense OE?0.80 (0.64–1.02)

0≤0.61.4

Synonymous OE?0.84

0≤1.21.6

LoF obs/exp: 2 / 5.9Missense obs/exp: 48 / 59.9Syn Z: 0.54

Background carrier burden — how many people carry a rare variant somewhere in BOLA3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 180

163 rare PASS variants

Rare truncating (LoF)

1 in 2,800

27 rare PASS variants

Rare synonymous (reference)

1 in 1,100

44 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for BOLA3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 8 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 280	1 in 2,400
South Asian	~43k	1 in 470	1 in 3,000
Remaining (unassigned)	~30k	1 in 180	1 in 1,900
European (Finnish)	~27k	1 in 700	1 in 2,800
Admixed American	~22k	1 in 440	≈ 1 in 5,700
African / African American	~21k	1 in 230	≈ 1 in 15,000
East Asian	~20k	1 in 270	1 in 4,000
Middle Eastern	~2,884	1 in 270	none seen

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): 3 of 4 coding exons well covered in gnomAD exomes; exon 2 marginal. Genomes: all 4.? see exons ↓