NDUFB4

Chr 3

NADH:ubiquinone oxidoreductase subunit B4

Also known as: B15, CI-B15

NCBI Gene: 4710 ENSG00000065518 UniProt: O95168 OMIM: 603840

This gene encodes an accessory subunit of mitochondrial complex I (NADH dehydrogenase), which transfers electrons from NADH to ubiquinone in the electron transport chain. Mutations cause mitochondrial complex I deficiency with autosomal recessive inheritance, typically presenting in infancy or early childhood with neurological symptoms, developmental delay, and multi-organ involvement. The gene shows low constraint to loss-of-function variants, consistent with recessive disease requiring biallelic mutations.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a non-catalytic subunit of the multisubunit NADH:ubiquinone oxidoreductase, the first enzyme complex in the mitochondrial electron transport chain (complex I). Mammalian complex I is composed of 45 different subunits and transfers electrons from NADH to ubiquinone. [provided by RefSeq, Dec 2009]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.43

Clinical Summary— NDUFB4

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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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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.43LOEUF

pLI 0.006

Z-score 0.85

OE 0.63 (0.31–1.43)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.39Z-score

OE missense 1.13 (0.94–1.35)

82 obs / 72.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.63 (0.31–1.43)

0≤0.351.4

Missense OE?1.13 (0.94–1.35)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 4 / 6.3Missense obs/exp: 82 / 72.7Syn Z: 0.32

This gene — mechanism propensity

0.83top 10%

GOF

0.6930th %ile

LOF

0.1894th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction 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.