ETFA

protein-coding

electron transfer flavoprotein subunit alpha

Gene summary

ETFA participates in catalyzing the initial step of the mitochondrial fatty acid beta-oxidation. It shuttles electrons between primary flavoprotein dehydrogenases and the membrane-bound electron transfer flavoprotein ubiquinone oxidoreductase. Defects in electron-transfer-flavoprotein have been implicated in type II glutaricaciduria in which multiple acyl-CoA dehydrogenase deficiencies result in large excretion of glutaric, lactic, ethylmalonic, butyric, isobutyric, 2-methyl-butyric, and isovaleric acids. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_000126.4

Inheritance

ClinVar variants

P:94U:128B:138

Top phenotype

Multiple acyl-CoA dehydrogenase deficiency (Glutaric aciduria IIA)

gnomAD constraint

pLI —, LoF o/e 0.38

Max pathogenic AF

—

Genomic locus

chr15:76,188,555-76,311,730

External References & Databases

Ensembl (ENSG00000140374)

Transcript & Mutation Effects

hg38 • Region Span ~123.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

multiple acyl-CoA dehydrogenase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009282

Submitter: ClinGen

ETFA was first reported in relation to autosomal recessive multiple acyl-CoA dehydrogenase deficiency in 1991 (Indo et al., PMID: 1882842]). Eighteen variants (missense, nonsense, frameshift, splicing) that have been reported in 12 probands in 6 publications (PMIDs: 12815589, 18289905,1430199, 20736750, 20023066, 16510302) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. Multiple acyl-CoA dehydrogenase deficiency is characterized by episodes of lethargy, vomiting, hypoglycemia, metabolic acidosis, and hepatomegaly often preceded by metabolic stress. The disease mechanism appears to be biallelic loss of function. Heterozygous carriers are reportedly unaffected. This gene-disease relationship is also supported by the interaction with ETFB, which is definitively associated with multiple acyl-CoA dehydrogenase deficiency, functional assays in patient cells showing reduced fatty acid oxidation, and a zebrafish model (PMIDs: 15159392, 23785301, 12815589). In summary, there is definitive evidence supporting the relationship between ETFA and autosomal recessive multiple acyl-CoA dehydrogenase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Fatty Acid Oxidation Disorders GCEP on May 22nd, 2018 (SOP Version 6). ETFA: Data provided by the ClinGen Prenatal GCEP from July 9, 2025 secondary analysis: Multiple acyl-CoA dehydrogenation deficiency (MADD) is an autosomal recessive disorder of fatty acid oxidation due to deficiency of the mitochondrial electron transfer chain. MADD can be caused by deficiencies in any of three proteins within the electron transfer flavoprotein (ETF) system, including ETFA, ETFB, and ETFDH. Pathogenic variants in the ETFA gene are responsible for approximately 5% of cases of MADD. Although genetically heterogeneous, there does not appear to be a difference in clinical phenotypes. The severity of disease is correlated with residual protein function and ranges from a severe neonatal form with or without congenital anomalies to a milder, later onset form. Neonatal forms present with hypotonia, severe metabolic acidosis, hyperammonemia, hypoglycemia, respiratory distress, hepatomegaly, and a sweaty feet odor. Prenatal features and congenital physical anomalies can include cystic/dysplastic kidneys with sequelae of oligohydramnios/anhydramnios, hypertrophic cardiomyopathy, dysmorphic facial features including midface hypoplasia, tented upper lip, low set ears, or high anterior hairline. Most severely affected newborns die in the first week of life. (PMID: 36406819, 18289905, 39234693, 35065907).

multiple acyl-CoA dehydrogenase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009282

Submitter: PanelApp Australia

multiple acyl-CoA dehydrogenase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009282

Submitter: Natera

multiple acyl-CoA dehydrogenase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009282

Submitter: G2P

multiple acyl-CoA dehydrogenase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009282

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Multiple acyl-CoA dehydrogenase deficiency (Glutaric aciduria IIA)AR

Manifestation: Biochemical; Gastrointestinal; Musculoskeletal; Neurologic; Renal

Intervention: Biochemical

Rationale: Dietary measures (fasting avoidance and low-fat diet, as well as supplementation, such as with riboflavin and carnitine) may be beneficial

Refs: 7145508; 8771170; 1882842; 1430199; 12815589; 18289905; 20736750; 22231380

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ETFA variants in ClinVar

9 Conditions Cataloged

Multiple acyl-CoA dehydrogenase deficiencyTotal: 476

not providedTotal: 80

Glutaric acidemia type 2ATotal: 66

not specifiedTotal: 44

Inborn genetic diseasesTotal: 30

ETFA-related disorderTotal: 11

ETFA-related disordersTotal: 8

Glutaric acidemia IIaTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000126.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			5 clinvar	132 clinvar		137
missense	1 clinvar	9 clinvar	119 clinvar	6 clinvar		135
nonsense	3 clinvar	10 clinvar	1 clinvar			14
start loss	2 clinvar	3 clinvar				5
frameshift	12 clinvar	27 clinvar	1 clinvar			40
splice donor/acceptor (+/-2bp)	1 clinvar	26 clinvar	2 clinvar			29
Total	19	75	128	138	0	360

Highest pathogenic variant AF is 0.000062072555

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 106 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000126.4	RefSeq	NP_000117.1	12	MANE Select
ENST00000557943.6	Ensembl	ENSP00000452762.1	12	MANE Select
NM_001127716.2	RefSeq	NP_001121188.1	11	Standard
ENST00000267950.12	Ensembl	ENSP00000267950.8	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
etfa	Danio rerio	Structure: Mauthner neuron Quality: swollen abnormal

Gene / Model

Organism

Observed Phenotype

etfa

Danio rerio

Structure: Mauthner neuron

Quality: swollen

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Respiratory electron transport
The citric acid (TCA) cycle and respiratory electron transport
Metabolism
Respiratory electron transport, ATP synthesis by chemiosmotic coupling, and heat production by uncoupling proteins.

Biological Process

electron transport chain
fatty acid beta-oxidation using acyl-CoA dehydrogenase

Molecular Function

protein binding
electron transfer activity
oxidoreductase activity
flavin adenine dinucleotide binding

Cellular Component

mitochondrion
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000557943
Coding exons: 12
Length: 96118
Individuals with no LoFs: 125688
Homozygous LoFs: 0
Heterozygous LoFs: 60
Defined: 125748
p: 0.000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.06	139	179	0.776	0.00000865	2118
Missense (PolyPhen)		62	78.882	0.78599		917
Synonymous	0.891	53	61.9	0.856	0.00000291	678
Loss of Function	2.66	8	21.2	0.377	0.00000113	246

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00031	0.00031	rare
South Asian	0.00046	0.00046	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Heterodimeric electron transfer flavoprotein that accepts electrons from several mitochondrial dehydrogenases, including acyl-CoA dehydrogenases, glutaryl-CoA and sarcosine dehydrogenase (PubMed:27499296, PubMed:15159392, PubMed:15975918, PubMed:9334218, PubMed:10356313). 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:1882842, PubMed:1430199). {ECO:0000269|PubMed:10356313, ECO:0000269|PubMed:12815589, ECO:0000269|PubMed:1430199, ECO:0000269|PubMed:15159392, ECO:0000269|PubMed:15975918, ECO:0000269|PubMed:27499296, ECO:0000269|PubMed:9334218, ECO:0000303|PubMed:17941859, ECO:0000305|PubMed:1882842}.;
Disease: DISEASE: Glutaric aciduria 2A (GA2A) [MIM:231680]: An autosomal recessively inherited disorder of fatty acid, amino acid, and choline metabolism. It is characterized by multiple acyl-CoA dehydrogenase deficiencies resulting in large excretion not only of glutaric acid, but also of lactic, ethylmalonic, butyric, isobutyric, 2-methyl-butyric, and isovaleric acids. {ECO:0000269|PubMed:12815589, ECO:0000269|PubMed:1430199, ECO:0000269|PubMed:1882842, ECO:0000269|PubMed:9334218}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.730

Intolerance Scores

LoFtool: 0.245
RVIS EVS: 0.08
RVIS percentile EVS: 60.09

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.924

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium