ETFA

Chr 15AR

electron transfer flavoprotein subunit alpha

ENSG00000140374 UniProt: P13804 OMIM: 608053

The ETFA protein forms part of the electron transfer flavoprotein complex that accepts electrons from multiple mitochondrial dehydrogenases and transfers them to the respiratory chain, playing an essential role in fatty acid oxidation and amino acid metabolism. Biallelic mutations cause glutaric acidemia type IIA, an autosomal recessive disorder affecting mitochondrial energy metabolism. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.68), and affected individuals typically present with metabolic acidosis and distinctive organic acid profiles.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Heterodimeric electron transfer flavoprotein that accepts electrons from several mitochondrial dehydrogenases, including acyl-CoA dehydrogenases, glutaryl-CoA and sarcosine dehydrogenase (PubMed:10356313, PubMed:15159392, PubMed:15975918, PubMed:27499296, PubMed:9334218). It transfers the electrons to the main mitochondrial respiratory chain via ETF-ubiquinone oxidoreductase (ETF dehydrogenase) (PubMed:9334218). Required for normal mitochondrial fatty acid oxidation and normal amino acid metabolism (PubMed:12815589, PubMed:1430199, PubMed:1882842)

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.681 OMIM phenotype

Clinical Summary— ETFA

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Gene-Disease Validity (ClinGen)

multiple acyl-CoA dehydrogenase deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — 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?

0.68LOEUF

pLI 0.003

Z-score 2.66

OE 0.38 (0.22–0.68)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.06Z-score

OE missense 0.78 (0.68–0.89)

139 obs / 179.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.38 (0.22–0.68)

0≤0.351.4

Missense OE?0.78 (0.68–0.89)

0≤0.61.4

Synonymous OE?0.86

0≤1.21.6

LoF obs/exp: 8 / 21.2Missense obs/exp: 139 / 179.0Syn Z: 0.89

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveETFA-related glutaric aciduriaLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6744th %ile

GOF

0.5367th %ile

LOF

0.3551th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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