NDUFB3

Chr 2AR

NADH:ubiquinone oxidoreductase subunit B3

Also known as: B12, CI-B12, MC1DN25

NCBI Gene: 4709 ENSG00000119013 UniProt: O43676 OMIM: 603839

This protein is an accessory subunit of mitochondrial Complex I (NADH dehydrogenase), which transfers electrons from NADH to the respiratory chain as the first enzyme in mitochondrial electron transport. Mutations cause mitochondrial complex I deficiency with autosomal recessive inheritance. The gene shows low constraint to loss-of-function variation (pLI ~0, LOEUF 1.94), consistent with the recessive inheritance pattern where heterozygous carriers are typically unaffected.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes an accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which is the first enzyme in the electron transport chain of mitochondria. This protein localizes to the inner membrane of the mitochondrion as a single-pass membrane protein. Mutations in this gene contribute to mitochondrial complex 1 deficiency. Alternative splicing results in multiple transcript variants encoding the same protein. Humans have multiple pseudogenes of this gene. [provided by RefSeq, Mar 2012]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Mitochondrial complex I deficiency, nuclear type 25MIM #618246

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · mitochondrial disease · AR · ClinGen 2022

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

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Pubs (1 yr)

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P/LP submissions

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P/LP missense

1.94

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.94LOEUF

pLI 0.000

Z-score -1.10

OE 1.61 (0.79–1.94)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.32Z-score

OE missense 0.88 (0.69–1.12)

45 obs / 51.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?1.61 (0.79–1.94)

0≤0.351.4

Missense OE?0.88 (0.69–1.12)

0≤0.61.4

Synonymous OE?0.70

0≤1.21.6

LoF obs/exp: 6 / 3.7Missense obs/exp: 45 / 51.4Syn Z: 0.98

Background carrier burden — how many people carry a rare variant somewhere in NDUFB3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 260

102 rare PASS variants

Rare truncating (LoF)

1 in 2,400

18 rare PASS variants

Rare synonymous (reference)

1 in 2,200

33 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NDUFB3. 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 520	1 in 2,100
South Asian	~43k	1 in 400	1 in 2,000
Remaining (unassigned)	~30k	1 in 190	1 in 3,000
European (Finnish)	~27k	1 in 3,800	none seen
Admixed American	~22k	1 in 230	1 in 2,800
African / African American	~21k	1 in 470	≈ 1 in 5,900
East Asian	~20k	1 in 760	≈ 1 in 20,000
Ashkenazi Jewish	~13k	1 in 770	none seen
Middle Eastern	~2,873	≈ 1 in 720	≈ 1 in 2,900

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): All 2 coding exons well covered in gnomAD exomes and genomes.? see exons ↓