ETFDH

electron transfer flavoprotein dehydrogenase

Basic information

Region (hg38): 4:158671968-158710742

Links

ENSG00000171503 ∙ NCBI:2110 ∙ OMIM:231675 ∙ HGNC:3483 ∙ Uniprot:Q16134 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• multiple acyl-CoA dehydrogenase deficiency (Definitive), mode of inheritance: AR
• multiple acyl-CoA dehydrogenase deficiency (Strong), mode of inheritance: AR
• multiple acyl-CoA dehydrogenase deficiency (Definitive), mode of inheritance: AR
• multiple acyl-CoA dehydrogenase deficiency (Strong), mode of inheritance: AR
• multiple acyl-CoA dehydrogenase deficiency (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Multiple acyl-CoA dehydrogenase deficiency (Glutaric aciduria IIC)	AR	Biochemical	Dietary measures (fasting avoidance and low-fat diet, as well as supplementation, such as with riboflavin and carnitine) may be beneficial	Biochemical; Gastrointestinal; Musculoskeletal; Neurologic; Renal	7145508; 8771170; 12815589; 16527485; 17412732; 17584774; 18289905; 19208393; 19249206; 19758981; 19783111; 20138856; 20370797; 20837308; 21088898; 21616504; 21907580; 22041377; 22231380; 22664151; 23106979; 23893693

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ETFDH gene.

• Multiple acyl-CoA dehydrogenase deficiency (94 variants)
• not provided (9 variants)
• Glutaric acidemia type 2C (6 variants)
• Glutaric acidemia IIc (5 variants)
• Abnormality of metabolism/homeostasis (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ETFDH gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			4	216		220
missense	24	65	184	4	1	278
nonsense	25	17				42
start loss	3		1			4
frameshift	39	36				75
inframe indel	1	2	2			5
splice donor/acceptor (+/-2bp)	5	31		1	1	38
splice region	1	4	7	42	3	57
non coding			12	119	16	147
Total	97	151	203	340	18

Highest pathogenic variant AF is 0.0000788

Variants in ETFDH

This is a list of pathogenic ClinVar variants found in the ETFDH region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
4-158672031-A-G			Likely benign (Sep 17, 2018)
4-158672047-A-G			Likely benign (Sep 17, 2018)
4-158672142-G-A		Multiple acyl-CoA dehydrogenase deficiency	Uncertain significance (Jun 14, 2016)
4-158672218-G-A		Multiple acyl-CoA dehydrogenase deficiency	Likely benign (Sep 17, 2018)
4-158672283-A-G		Multiple acyl-CoA dehydrogenase deficiency	Uncertain significance (Jun 14, 2016)
4-158672360-G-A		Multiple acyl-CoA dehydrogenase deficiency	Uncertain significance (Jan 12, 2018)
4-158672380-C-G		Multiple acyl-CoA dehydrogenase deficiency	Uncertain significance (Jan 13, 2018)
4-158672382-A-G		not specified	Uncertain significance (Mar 14, 2024)
4-158672396-C-T		Multiple acyl-CoA dehydrogenase deficiency	Uncertain significance (Oct 13, 2021)
4-158672414-GTCC-G		not specified	Likely benign (Oct 26, 2017)
4-158672458-T-C		Glutaric acidemia IIc • Multiple acyl-CoA dehydrogenase deficiency	Pathogenic (Apr 09, 2023)
4-158672458-T-G		See cases	Uncertain significance (-)
4-158672459-G-C		Multiple acyl-CoA dehydrogenase deficiency	Pathogenic (Jul 19, 2022)
4-158672459-G-T		Multiple acyl-CoA dehydrogenase deficiency	Pathogenic (Jul 25, 2023)
4-158672462-G-C		Multiple acyl-CoA dehydrogenase deficiency	Likely benign (Nov 10, 2020)
4-158672468-G-A		Multiple acyl-CoA dehydrogenase deficiency • Glutaric acidemia type 2C	Conflicting classifications of pathogenicity (Jan 09, 2024)
4-158672471-A-G		Multiple acyl-CoA dehydrogenase deficiency	Likely benign (Oct 30, 2022)
4-158672477-G-A		Multiple acyl-CoA dehydrogenase deficiency	Likely benign (Dec 19, 2023)
4-158672478-C-G		not specified	Likely benign (Dec 04, 2012)
4-158672480-G-T		Multiple acyl-CoA dehydrogenase deficiency	Likely benign (Jan 07, 2023)
4-158672481-T-A		Multiple acyl-CoA dehydrogenase deficiency	Uncertain significance (Feb 23, 2024)
4-158672483-C-T		Multiple acyl-CoA dehydrogenase deficiency	Likely benign (Nov 09, 2019)
4-158672488-T-C			Uncertain significance (Sep 15, 2022)
4-158672490-G-C		Multiple acyl-CoA dehydrogenase deficiency	Pathogenic/Likely pathogenic (Apr 27, 2023)
4-158672491-G-A		Multiple acyl-CoA dehydrogenase deficiency	Likely pathogenic (Aug 12, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ETFDH	protein_coding	protein_coding	ENST00000511912	13	37499

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.78e-13	0.428	125610	0	137	125747	0.000545

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.393	314	334	0.940	0.0000166	4022
Missense in Polyphen		139	148.76	0.93436		1713
Synonymous	-0.163	119	117	1.02	0.00000609	1196
Loss of Function	1.36	24	32.3	0.742	0.00000152	397

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00182	0.00181
Ashkenazi Jewish	0.000604	0.000496
East Asian	0.000165	0.000163
Finnish	0.0000962	0.0000924
European (Non-Finnish)	0.000611	0.000607
Middle Eastern	0.000165	0.000163
South Asian	0.000199	0.000196
Other	0.000509	0.000489

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Accepts electrons from ETF and reduces ubiquinone.
• Disease: DISEASE: Glutaric aciduria 2C (GA2C) [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:12359134, ECO:0000269|PubMed:12815589, ECO:0000269|PubMed:16527485, ECO:0000269|PubMed:17412732, ECO:0000269|PubMed:19249206, ECO:0000269|PubMed:20370797}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: 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. (Consensus)

Recessive Scores

• pRec: 0.315

Intolerance Scores

• loftool: 0.286
• rvis_EVS: -0.56
• rvis_percentile_EVS: 19.54

Haploinsufficiency Scores

• pHI: 0.0543
• hipred: N
• hipred_score: 0.333
• ghis: 0.550

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.951

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Etfdh
• Phenotype: behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); vision/eye phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span)

Zebrafish Information Network

• Gene name: etfdh
• Affected structure: glial cell
• Phenotype tag: abnormal
• Phenotype quality: malformed

Gene ontology

• Biological process: response to oxidative stress;electron transport chain;respiratory electron transport chain;fatty acid beta-oxidation using acyl-CoA dehydrogenase
• Cellular component: mitochondrial matrix;integral component of mitochondrial inner membrane;mitochondrial membrane
• Molecular function: electron-transferring-flavoprotein dehydrogenase activity;electron transfer activity;oxidoreductase activity;oxidoreductase activity, oxidizing metal ions with flavin as acceptor;metal ion binding;quinone binding;ubiquinone binding;flavin adenine dinucleotide binding;4 iron, 4 sulfur cluster binding