ETFA

Summary

ETFA (electron transfer flavoprotein subunit alpha, HGNC:3481) is a protein-coding gene on chromosome 15q24.2-q24.3, encoding Electron transfer flavoprotein subunit alpha, mitochondrial (P13804). Heterodimeric electron transfer flavoprotein that accepts electrons from several mitochondrial dehydrogenases, including acyl-CoA dehydrogenases, glutaryl-CoA and sarcosine dehydrogenase.

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.

Source: NCBI Gene 2108 — RefSeq curated summary.

At a glance

• Gene–disease (curated): multiple acyl-CoA dehydrogenase deficiency (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 36
• Clinical variants (ClinVar): 1,041 total — 41 pathogenic, 73 likely-pathogenic
• Phenotypes (HPO): 129
• Druggable target: yes
• MANE Select transcript: NM_000126

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3481
Approved symbol	ETFA
Name	electron transfer flavoprotein subunit alpha
Location	15q24.2-q24.3
Locus type	gene with protein product
Status	Approved
Aliases	GA2, EMA, MADD
Ensembl gene	ENSG00000140374
Ensembl biotype	protein_coding
OMIM	608053
Entrez	2108

Gene structure

Transcript identifiers

Ensembl transcripts: 43 — 16 protein_coding, 14 nonsense_mediated_decay, 9 retained_intron, 4 protein_coding_CDS_not_defined

ENST00000267950, ENST00000433983, ENST00000557943, ENST00000557975, ENST00000558803, ENST00000559075, ENST00000559386, ENST00000559602, ENST00000559758, ENST00000559973, ENST00000560044, ENST00000560179, ENST00000560309, ENST00000560345, ENST00000560595, ENST00000560726, ENST00000560816, ENST00000560899, ENST00000561092, ENST00000565910, ENST00000685118, ENST00000685548, ENST00000685863, ENST00000687293, ENST00000687975, ENST00000688154, ENST00000688389, ENST00000688637, ENST00000688908, ENST00000689120, ENST00000689730, ENST00000689739, ENST00000690610, ENST00000691021, ENST00000691071, ENST00000691695, ENST00000692691, ENST00000693064, ENST00000901535, ENST00000901536, ENST00000901537, ENST00000901538, ENST00000925698

RefSeq mRNA: 2 — MANE Select: NM_000126 NM_000126, NM_001127716

CCDS: CCDS32299, CCDS45311

Canonical transcript exons

ENST00000557943 — 12 exons

Exon	Start	End
ENSE00001382235	76311350	76311469
ENSE00002546770	76215353	76216597
ENSE00003466049	76286371	76286481
ENSE00003481087	76292619	76292700
ENSE00003502108	76285637	76285738
ENSE00003521140	76292431	76292513
ENSE00003530387	76231333	76231398
ENSE00003542133	76274412	76274494
ENSE00003557515	76283757	76283825
ENSE00003625053	76225849	76225929
ENSE00003641732	76287846	76287945
ENSE00003683241	76295591	76295737

Expression profiles

Bgee: expression breadth ubiquitous, 297 present calls, max score 99.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 72.2235 / max 530.7287, expressed in 1824 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
151012	70.7581	1824
151013	1.4654	861

Top tissues by expression

298 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	99.76	gold quality
secondary oocyte	CL:0000655	99.64	gold quality
jejunal mucosa	UBERON:0000399	99.30	gold quality
mucosa of transverse colon	UBERON:0004991	99.22	gold quality
right adrenal gland cortex	UBERON:0035827	99.06	gold quality
right adrenal gland	UBERON:0001233	99.04	gold quality
heart left ventricle	UBERON:0002084	99.04	gold quality
cardiac ventricle	UBERON:0002082	99.02	gold quality
heart right ventricle	UBERON:0002080	99.00	gold quality
gastrocnemius	UBERON:0001388	98.97	gold quality
right lobe of liver	UBERON:0001114	98.95	gold quality
muscle of leg	UBERON:0001383	98.85	gold quality
left adrenal gland	UBERON:0001234	98.84	gold quality
jejunum	UBERON:0002115	98.82	gold quality
rectum	UBERON:0001052	98.77	gold quality
duodenum	UBERON:0002114	98.77	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.76	gold quality
muscle organ	UBERON:0001630	98.73	gold quality
right atrium auricular region	UBERON:0006631	98.73	gold quality
skeletal muscle organ	UBERON:0014892	98.73	gold quality
left adrenal gland cortex	UBERON:0035825	98.73	gold quality
biceps brachii	UBERON:0001507	98.71	gold quality
adrenal cortex	UBERON:0001235	98.66	gold quality
apex of heart	UBERON:0002098	98.66	gold quality
heart	UBERON:0000948	98.65	gold quality
cardiac atrium	UBERON:0002081	98.64	gold quality
liver	UBERON:0002107	98.64	gold quality
diaphragm	UBERON:0001103	98.63	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.63	gold quality
adrenal tissue	UBERON:0018303	98.63	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

25 targeting ETFA, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111
HSA-MIR-4679	99.76	69.19	1229
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-642A-5P	99.51	65.10	1152
HSA-MIR-302B-5P	99.50	69.49	1857
HSA-MIR-302D-5P	99.50	69.34	1863
HSA-MIR-147B-5P	99.45	70.62	2432
HSA-MIR-4799-3P	97.78	65.97	893
HSA-MIR-4720-5P	97.46	65.67	893
HSA-MIR-5588-5P	97.46	65.70	913
HSA-MIR-4445-5P	97.21	66.16	832

Literature-anchored findings (GeneRIF, showing 14)

• These studies indicate that a series of conformational changes occur during the assembly of the TMADH.ETF electron transfer complex and that the kinetics of assembly observed with mutant TMADH or ETF complexes are much slower (PMID:11756429)
• Tissue samples from 16 unrelated patients with ETF deficiency were analysed and the majority of the patients had mutations in the ETFA gene. (PMID:16510302)
• No mutations in electron-transfer-flavoprotein but maternal riboflavin deficiency led to multiple acyl-CoA dehydrogenation deficiency (PMID:17689999)
• Data established structural hotspots within the ETF fold, and provided a rationale for the prediction of effects of mutations in ETF. (PMID:20674745)
• investigations are compatible with the notion that the ETFalpha-T171 variant displays an altered conformational landscape that results in reduced protein function under thermal stress (PMID:21219902)
• These results are consistent with the electron transfer flavoprotein alpha II domain adopting orientations in solution that deviate from the crystal structure of free ETF towards the active, substrate-bound orientation. (PMID:21308847)
• the mechanism of tert-butyl hydroperoxide-induced an apoptosis cascade and endoplasmic reticulum stress in hepatocyte cells by up-regulation of ETFA, providing a new mechanism for liver injury. (PMID:24394546)
• our results indicate that genetic variants in ETFA may modify individual susceptibility to non-GBM of glioma in the Han Chinese population and support the role of the ETFA genes in the occurrence of glioma. (PMID:28320150)
• Data suggest that ETF (heterodimer of ETFA and ETFB) catalyzes irreversible and pH-dependent oxidation of 8alpha-methyl group of FAD to form to 8-formyl-FAD (8f-FAD). (PMID:29301933)
• Molecular and Clinical Investigations on Portuguese Patients with Multiple acyl-CoA Dehydrogenase Deficiency. (PMID:31418342)
• Molecular Oxygen Binding in the Mitochondrial Electron Transfer Flavoprotein. (PMID:31665600)
• A case report of a mild form of multiple acyl-CoA dehydrogenase deficiency due to compound heterozygous mutations in the ETFA gene. (PMID:31996215)
• Screening of multiple acyl-CoA dehydrogenase deficiency in newborns and follow-up of patients. (PMID:34704421)
• Platelet Microparticle-Derived MiR-320b Inhibits Hypertension with Atherosclerosis Development by Targeting ETFA. (PMID:38556340)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	etfa	ENSDARG00000101631
mus_musculus	Etfa	ENSMUSG00000032314
rattus_norvegicus	Etfa	ENSRNOG00000015233

Protein

Protein identifiers

Electron transfer flavoprotein subunit alpha, mitochondrial — P13804 (reviewed: P13804)

All UniProt accessions (20): P13804, A0A0S2Z3L0, A0A0S2Z3M4, A0A8I5KSA0, A0A8I5KT03, A0A8I5KU27, A0A8I5KUF3, A0A8I5KUR2, A0A8I5KVC9, A0A8I5KVL5, A0A8I5KYH4, A0A8I5KYP7, H0YK49, H0YKF0, H0YL83, H0YLU7, H0YM12, H0YMU8, H3BV91, J3KN60

UniProt curated annotations — full annotation on UniProt →

Function. Heterodimeric electron transfer flavoprotein that accepts electrons from several mitochondrial dehydrogenases, including acyl-CoA dehydrogenases, glutaryl-CoA and sarcosine dehydrogenase. It transfers the electrons to the main mitochondrial respiratory chain via ETF-ubiquinone oxidoreductase (ETF dehydrogenase). Required for normal mitochondrial fatty acid oxidation and normal amino acid metabolism.

Subunit / interactions. Heterodimer composed of ETFA and ETFB. Identified in a complex that contains ETFA, ETFB and ETFRF1. Interaction with ETFRF1 promotes dissociation of the bound FAD and loss of electron transfer activity. Interacts with TASOR. Interacts with MBTPS1; the interaction stabilizes the ETFA/ETFB heterodimer and promotes FAD binding.

Subcellular location. Mitochondrion matrix.

Post-translational modifications. The N-terminus is blocked.

Disease relevance. 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. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 FAD per dimer.

Domain organisation. Domain I shares an identical polypeptide fold with the beta subunit ETFB though there is no sequence similarity.

Similarity. Belongs to the ETF alpha-subunit/FixB family.

Isoforms (2)

UniProt ID	Names	Canonical?
P13804-1	1	yes
P13804-2	2

RefSeq proteins (2): NP_000117, NP_001121188 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001308	ETF_a/FixB	Family
IPR014729	Rossmann-like_a/b/a_fold	Homologous_superfamily
IPR014730	ETF_a/b_N	Domain
IPR014731	ETF_asu_C	Domain
IPR018206	ETF_asu_C_CS	Conserved_site
IPR029035	DHS-like_NAD/FAD-binding_dom	Homologous_superfamily
IPR033947	ETF_alpha_N	Domain

Pfam: PF00766, PF01012

UniProt features (76 total): modified residue 24, strand 19, helix 15, binding site 6, sequence variant 4, region of interest 2, turn 2, transit peptide 1, chain 1, splice variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
1EFV	X-RAY DIFFRACTION	2.1
2A1U	X-RAY DIFFRACTION	2.11
2A1T	X-RAY DIFFRACTION	2.8
1T9G	X-RAY DIFFRACTION	2.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P13804-F1	94.00	0.91

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (6): 223; 248; 263–266; 281–286; 300; 318–319

Post-translational modifications (24): 59, 59, 62, 69, 69, 75, 85, 85, 93, 101, 139, 140, 158, 158, 164, 187, 203, 203, 216, 226 …

Mutagenesis-validated functional residues (1):

Position	Phenotype
249	loss of electron transfer activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-611105	Respiratory electron transport

MSigDB gene sets: 639 (showing top): GOBP_LIPID_MODIFICATION, MODULE_93, GOBP_FATTY_ACID_CATABOLIC_PROCESS, ROVERSI_GLIOMA_COPY_NUMBER_UP, MORF_RAD21, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, LINDGREN_BLADDER_CANCER_CLUSTER_3_DN, SCHLESINGER_METHYLATED_DE_NOVO_IN_CANCER, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, RACCACAR_AML_Q6, TGACCTY_ERR1_Q2, REACTOME_MEMBRANE_TRAFFICKING, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GGAMTNNNNNTCCY_UNKNOWN

GO Biological Process (3): amino acid catabolic process (GO:0009063), respiratory electron transport chain (GO:0022904), fatty acid beta-oxidation using acyl-CoA dehydrogenase (GO:0033539)

GO Molecular Function (4): electron transfer activity (GO:0009055), oxidoreductase activity (GO:0016491), flavin adenine dinucleotide binding (GO:0050660), protein binding (GO:0005515)

GO Cellular Component (3): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), electron transfer flavoprotein complex (GO:0045251)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Aerobic respiration and respiratory electron transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	2
amino acid metabolic process	1
catabolic process	1
electron transport chain	1
cellular respiration	1
acyl-CoA dehydrogenase activity	1
fatty acid beta-oxidation	1
molecular_function	1
catalytic activity	1
nucleotide binding	1
anion binding	1
binding	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1
protein-containing complex	1

Protein interactions and networks

STRING

2814 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ETFA	ETFB	P38117	999
ETFA	ETFDH	Q16134	995
ETFA	GM2A	P17900	931
ETFA	B4GALNT1	Q00973	871
ETFA	NPC1	O15118	785
ETFA	ACADS	P16219	644
ETFA	ETFRF1	Q6IPR1	623
ETFA	FLAD1	Q8NFF5	612
ETFA	NDUFAB1	O14561	590
ETFA	UQCRC2	P22695	588
ETFA	HADH	Q16836	573
ETFA	GABBR2	O75899	571
ETFA	ACADVL	P49748	571
ETFA	ACADM	P11310	556
ETFA	PCCB	P05166	550

IntAct

156 interactions, top by confidence:

A	B	Type	Score
ETFA	ETFB	psi-mi:“MI:0915”(physical association)	0.810
ETFA	ETFB	psi-mi:“MI:0407”(direct interaction)	0.810
ETFA	ETFB	psi-mi:“MI:0914”(association)	0.810
ETFB	ETFA	psi-mi:“MI:0914”(association)	0.810
ETFB	ETFA	psi-mi:“MI:0407”(direct interaction)	0.810
ETFRF1	ETFA	psi-mi:“MI:0914”(association)	0.740
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
PRELID3B	TRIAP1	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
ETFRF1	NDUFAB1	psi-mi:“MI:0914”(association)	0.640
	PMPCB	psi-mi:“MI:0914”(association)	0.640
CFTR	ETFA	psi-mi:“MI:0915”(physical association)	0.640
SLC17A5	LGALS8	psi-mi:“MI:0914”(association)	0.640
HSCB	ETFA	psi-mi:“MI:0915”(physical association)	0.610
SLCO4C1	CLGN	psi-mi:“MI:0914”(association)	0.530
HSPA8	ARHGEF10	psi-mi:“MI:2364”(proximity)	0.480

BioGRID (383): ETFA (Affinity Capture-MS), ETFA (Affinity Capture-MS), NNT (Affinity Capture-MS), EIF2S2 (Affinity Capture-MS), GLS (Affinity Capture-MS), ETFB (Affinity Capture-MS), LYRM5 (Affinity Capture-MS), NDUFAB1 (Affinity Capture-MS), C8orf82 (Affinity Capture-MS), ALDH1B1 (Co-fractionation), APMAP (Co-fractionation), ARF4 (Co-fractionation), ARF5 (Co-fractionation), ARL8B (Co-fractionation), ATP5A1 (Co-fractionation)

ESM2 similar proteins: A2XNR6, A2ZCP0, A4HQ10, B2VZQ8, B6H5R4, B6TZD1, B9HCR2, O04130, O49485, O60027, O82662, P05165, P0CN60, P0CN61, P0DTA4, P13803, P13804, P29102, P49079, P53571, P54889, P55195, P78790, P93832, Q01637, Q0CFY3, Q0ITU1, Q0VFN1, Q12480, Q148D5, Q2KJE4, Q54FD7, Q5RC31, Q5Y223, Q6H6D2, Q6K669, Q6K9N6, Q75LJ3, Q8HXY0, Q8J112

Diamond homologs: A1A792, A2XNR6, A7ZHD5, A7ZVZ4, B1IRD4, B1LFX6, B1XBG7, B5BL14, B5F757, B5YYD6, B6HYZ3, B7L4G5, B7LWN3, B7M0D9, B7MAG5, B7MNP9, B7N7R7, B7NHE6, B7UI88, C4ZPW8, G3KIM6, O33096, P09819, P0CN60, P0CN61, P10449, P13803, P13804, P26483, P31574, P38974, P52039, P53571, P53573, P53574, P53578, P59674, P59675, P64095, P64096

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ETFA	“form complex”	ETF	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 144 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Mitochondrial protein import	10	17.1×	2e-07
Mitochondrial protein degradation	9	10.5×	4e-05
Signaling by BRAF and RAF1 fusions	5	8.7×	6e-03
Respiratory electron transport	6	5.8×	8e-03
Aerobic respiration and respiratory electron transport	6	5.4×	9e-03

GO biological processes:

GO term	Partners	Fold	FDR
JNK cascade	5	11.1×	9e-03
MAPK cascade	7	8.7×	3e-03
cellular response to hypoxia	7	6.9×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1041 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	41
Likely pathogenic	73
Uncertain significance	424
Likely benign	344
Benign	49

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069254	NM_000126.4(ETFA):c.793C>T (p.Gln265Ter)	Pathogenic
1076385	NM_000126.4(ETFA):c.478del (p.Asp160fs)	Pathogenic
1252024	NM_000126.4(ETFA):c.*27_*30del	Pathogenic
1326727	NM_001376571.1(MADD):c.710C>G (p.Ser237Ter)	Pathogenic
1422394	NM_000126.4(ETFA):c.427dup (p.Thr143fs)	Pathogenic
1443409	NM_000126.4(ETFA):c.285del (p.Ile96fs)	Pathogenic
1454539	NC_000015.9:g.(?76508890)(76603739_?)del	Pathogenic
1699228	NM_001376571.1(MADD):c.4109T>A (p.Leu1370Ter)	Pathogenic
2007565	NM_000126.4(ETFA):c.461dup (p.Cys155fs)	Pathogenic
2021532	NM_000126.4(ETFA):c.556G>T (p.Glu186Ter)	Pathogenic
2034094	NM_000126.4(ETFA):c.369dup (p.Ala124fs)	Pathogenic
2048411	NM_001376571.1(MADD):c.4594C>T (p.Arg1532Ter)	Pathogenic
2307248	NM_001376571.1(MADD):c.4392_4395del (p.Cys1464fs)	Pathogenic
2422389	NC_000015.9:g.(?76580177)(76585051_?)del	Pathogenic
2594	NM_000126.4(ETFA):c.797C>T (p.Thr266Met)	Pathogenic
2665104	NC_000011.10:g.(47329894_47331627)_(47335115_47335951)del	Pathogenic
2766888	NM_000126.4(ETFA):c.593_594del (p.Glu198fs)	Pathogenic
2785152	NM_000126.4(ETFA):c.37dup (p.Ala13fs)	Pathogenic
2819872	NM_000126.4(ETFA):c.560del (p.Lys187fs)	Pathogenic
2864511	NM_000126.4(ETFA):c.311_312del (p.Asn104fs)	Pathogenic
2894130	NM_000126.4(ETFA):c.597G>A (p.Trp199Ter)	Pathogenic
2901909	NM_000126.4(ETFA):c.322_323del (p.Ile108fs)	Pathogenic
3243763	NC_000015.9:g.(?76566733)(76566855_?)del	Pathogenic
3243764	NC_000015.9:g.(?76566733)(76603729_?)del	Pathogenic
3390921	NC_000015.10:g.76211811_76230784del	Pathogenic
3577725	NM_000126.4(ETFA):c.1A>G (p.Met1Val)	Pathogenic
3642543	NM_000126.4(ETFA):c.499del (p.Ser167fs)	Pathogenic
3724067	NM_000126.4(ETFA):c.373_376del (p.Ala125fs)	Pathogenic
4050443	NM_001376571.1(MADD):c.4286_4287del (p.Ser1429fs)	Pathogenic
635764	arr[hg19]11p11.2(47339995x2,47343435_47375684x1,47387184x2)	Pathogenic

SpliceAI

8918 predictions. Top by Δscore:

Variant	Effect	Δscore
11:47269747:GCGC:G	donor_gain	1.0000
11:47274559:TCAG:T	acceptor_loss	1.0000
11:47274560:CA:C	acceptor_loss	1.0000
11:47274561:A:AG	acceptor_gain	1.0000
11:47274561:A:AT	acceptor_loss	1.0000
11:47274561:AG:A	acceptor_gain	1.0000
11:47274562:G:GG	acceptor_gain	1.0000
11:47274562:GG:G	acceptor_gain	1.0000
11:47275895:TCAG:T	acceptor_loss	1.0000
11:47275897:A:AG	acceptor_gain	1.0000
11:47275897:AG:A	acceptor_gain	1.0000
11:47275898:G:GG	acceptor_gain	1.0000
11:47275898:GG:G	acceptor_gain	1.0000
11:47276860:GCAG:G	donor_gain	1.0000
11:47276861:CAGG:C	donor_loss	1.0000
11:47276862:AGG:A	donor_loss	1.0000
11:47276863:GGT:G	donor_loss	1.0000
11:47276864:G:C	donor_loss	1.0000
11:47276865:T:G	donor_loss	1.0000
11:47278153:T:G	acceptor_gain	1.0000
11:47278155:A:AG	acceptor_gain	1.0000
11:47278163:A:AG	acceptor_gain	1.0000
11:47278164:G:GG	acceptor_gain	1.0000
11:47278164:GCT:G	acceptor_gain	1.0000
11:47278277:GG:G	donor_gain	1.0000
11:47278278:GG:G	donor_gain	1.0000
11:47278279:G:C	donor_loss	1.0000
11:47278279:G:GG	donor_gain	1.0000
11:47278991:T:TA	acceptor_gain	1.0000
11:47278992:G:A	acceptor_gain	1.0000

AlphaMissense

2133 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:76231349:C:T	G289E	1.000
15:76231350:C:A	G289W	1.000
15:76231358:T:C	H286R	1.000
15:76231359:G:C	H286D	1.000
15:76231360:T:A	Q285H	1.000
15:76231360:T:G	Q285H	1.000
15:76231370:C:T	G282E	1.000
15:76231376:A:T	I280K	1.000
15:76274428:C:T	G267E	1.000
15:76274433:C:A	Q265H	1.000
15:76274433:C:G	Q265H	1.000
15:76274437:C:T	G264E	1.000
15:76274438:C:G	G264R	1.000
15:76274438:C:T	G264R	1.000
15:76274485:G:A	S248F	1.000
15:76225881:C:G	A311P	0.999
15:76225912:A:C	N300K	0.999
15:76225912:A:T	N300K	0.999
15:76231346:A:G	M290T	0.999
15:76231350:C:G	G289R	0.999
15:76231350:C:T	G289R	0.999
15:76231357:A:C	H286Q	0.999
15:76231357:A:T	H286Q	0.999
15:76231359:G:T	H286N	0.999
15:76231362:G:T	Q285K	0.999
15:76231370:C:A	G282V	0.999
15:76231371:C:G	G282R	0.999
15:76231371:C:T	G282R	0.999
15:76231373:G:T	S281Y	0.999
15:76231374:A:G	S281P	0.999

dbSNP variants (sampled 300 via entrez): RS1000002825 (15:76310225 T>C,G), RS1000047322 (15:76220793 T>A,C), RS1000064709 (15:76309251 C>G), RS1000066709 (15:76217657 G>A,C), RS1000081357 (15:76262619 A>C), RS1000123072 (15:76261499 A>C), RS1000148581 (15:76268716 A>G), RS1000175321 (15:76288068 C>T), RS1000202274 (15:76246848 A>G), RS1000208577 (15:76284666 A>G), RS1000315486 (15:76231781 A>T), RS1000331818 (15:76277105 C>T), RS1000337102 (15:76278491 C>T), RS1000352047 (15:76253739 T>C), RS1000406973 (15:76281458 C>G)

Disease associations

OMIM: gene MIM:608053 | disease phenotypes: MIM:231680, MIM:619004, MIM:619005, MIM:115197, MIM:209850, MIM:231690, MIM:615396

GenCC curated gene-disease

Disease	Classification	Inheritance
multiple acyl-CoA dehydrogenase deficiency	Definitive	Autosomal recessive
neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia	Strong	Autosomal recessive
deeah syndrome	Strong	Autosomal recessive
syndromic intellectual disability	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
multiple acyl-CoA dehydrogenase deficiency	Definitive	AR

Mondo (11): multiple acyl-CoA dehydrogenase deficiency (MONDO:0009282), deeah syndrome (MONDO:0033561), glutaric acidemia IIa (MONDO:0700073), neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia (MONDO:0033562), hypertrophic cardiomyopathy (MONDO:0005045), multiple acyl-CoA dehydrogenase deficiency, severe neonatal type (MONDO:0018332), hypertrophic cardiomyopathy 4 (MONDO:0007268), autism (MONDO:0005260), glutaric acidemia type 3 (MONDO:0009283), left ventricular noncompaction 10 (MONDO:0014163), syndromic intellectual disability (MONDO:0000508)

Orphanet (7): Multiple acyl-CoA dehydrogenase deficiency (Orphanet:26791), MADD-related developmental delay-endocrine dysfunction-hypohemoglobinemia syndrome (Orphanet:686495), Rare hypertrophic cardiomyopathy (Orphanet:217569), Multiple acyl-CoA dehydrogenase deficiency, severe neonatal type (Orphanet:394529), Glutaric acidemia type 3 (Orphanet:35706), Familial isolated dilated cardiomyopathy (Orphanet:154), Left ventricular noncompaction (Orphanet:54260)

HPO phenotypes

129 total (30 of 129 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000054	Micropenis
HP:0000078	Abnormality of the genital system
HP:0000113	Polycystic kidney dysplasia
HP:0000114	Proximal tubulopathy
HP:0000160	Narrow mouth
HP:0000189	Narrow palate
HP:0000218	High palate
HP:0000256	Macrocephaly
HP:0000260	Wide anterior fontanel
HP:0000268	Dolichocephaly
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000307	Pointed chin
HP:0000322	Short philtrum
HP:0000337	Broad forehead
HP:0000341	Narrow forehead
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000377	Abnormal pinna morphology
HP:0000430	Underdeveloped nasal alae
HP:0000463	Anteverted nares
HP:0000470	Short neck
HP:0000486	Strabismus
HP:0000506	Telecanthus
HP:0000519	Developmental cataract

GWAS associations

36 associations (top):

Study	Trait	p-value
GCST000288_7	HDL cholesterol	6.000000e-11
GCST000568_10	Fasting blood glucose	2.000000e-18
GCST001212_10	Proinsulin levels	1.000000e-88
GCST001212_9	Proinsulin levels	7.000000e-12
GCST001476_7	Response to tocilizumab in rheumatoid arthritis	7.000000e-07
GCST001527_23	Fasting blood glucose (BMI interaction)	4.000000e-12
GCST002899_34	HDL cholesterol	2.000000e-21
GCST003227_11	Non-glioblastoma glioma	6.000000e-09
GCST003374_2	Chronic kidney disease	3.000000e-06
GCST004347_16	Glioma	1.000000e-07
GCST004348_10	Non-glioblastoma glioma	2.000000e-13
GCST004521_165	Autism spectrum disorder or schizophrenia	3.000000e-08
GCST005186_22	Fasting blood glucose	4.000000e-13
GCST005232_56	Neuroticism	1.000000e-16
GCST005803_6	Corneal astigmatism	3.000000e-06
GCST006065_37	Glaucoma (primary open-angle)	9.000000e-10
GCST006479_152	Diverticular disease	1.000000e-07
GCST006479_153	Diverticular disease	7.000000e-06
GCST006923_11	Loneliness	1.000000e-07
GCST006924_13	Loneliness (MTAG)	1.000000e-08
GCST006979_937	Heel bone mineral density	6.000000e-09
GCST007576_355	Chronotype	2.000000e-13
GCST007576_390	Chronotype	4.000000e-12
GCST007614_53	C-reactive protein levels	9.000000e-13
GCST007709_284	General factor of neuroticism	9.000000e-11
GCST007825_4	Alzheimer’s disease or fasting glucose levels (pleiotropy)	3.000000e-16
GCST007899_13	Fasting blood glucose	5.000000e-12
GCST008109_1	Fasting blood proinsulin levels	8.000000e-15
GCST008109_3	Fasting blood proinsulin levels	5.000000e-25
GCST008109_6	Fasting blood proinsulin levels	3.000000e-08

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004467	insulin measurement
EFO:0004340	body mass index
EFO:0007660	neuroticism measurement
EFO:1002040	Corneal astigmatism
EFO:0009959	diverticular disease
EFO:0007865	loneliness measurement
EFO:0009270	heel bone mineral density
EFO:0008328	chronotype measurement
EFO:0004458	C-reactive protein measurement
EFO:0004469	HOMA-B
EFO:0007989	monocyte percentage of leukocytes

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D002312	Cardiomyopathy, Hypertrophic	C14.280.238.100; C14.280.484.048.750.070.160
C566169	Cardiomyopathy, Familial Hypertrophic, 4 (supp.)
C562818	Glutaric Aciduria III (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066955 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2279238	MADD, NR1H3	3	2.25	1	verapamil

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.03	Kd	92.8	nM	CHEMBL5653589
7.03	ED50	92.8	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148345: Binding affinity to human ETFA incubated for 45 mins by Kinobead based pull down assay	kd	0.0928	uM

CTD chemical–gene interactions

72 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, increases expression, affects cotreatment, increases abundance	3
sodium arsenite	affects cotreatment, increases expression, decreases expression	3
Air Pollutants	affects cotreatment, increases abundance, increases expression, affects expression, decreases expression	3
Benzo(a)pyrene	decreases expression, increases methylation	3
Tobacco Smoke Pollution	decreases expression, increases expression, affects expression	3
bisphenol F	decreases expression, increases expression, affects cotreatment	2
perfluorooctanoic acid	increases expression	2
Arsenic Trioxide	increases expression	2
Acetaminophen	affects cotreatment, decreases expression	2
Ozone	increases expression, increases abundance, affects expression, affects cotreatment	2
Rotenone	decreases expression	2
Valproic Acid	affects expression, increases methylation	2
aristolochic acid I	increases expression	1
napabucasin	decreases expression	1
ginger extract	affects cotreatment, affects expression, increases abundance	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases expression, increases abundance, affects cotreatment	1
pirinixic acid	affects binding, increases activity, increases expression	1
lead acetate	affects cotreatment, increases expression	1
nobiletin	decreases expression, decreases reaction	1
sodium arsenate	decreases reaction, decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, increases reaction	1
benzo(e)pyrene	increases methylation	1
gossypol acetic acid	decreases expression	1
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
chloropicrin	affects expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651387	Binding	Binding affinity to human ETFA incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2WR	Abcam HEK293T ETFA KO	Transformed cell line	Female

Clinical trials (associated diseases)

297 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00879060	PHASE4	COMPLETED	Clinical and Therapeutic Implications of Fibrosis in Hypertrophic Cardiomyopathy
NCT01721967	PHASE4	COMPLETED	Ranolazine for the Treatment of Chest Pain in HCM Patients
NCT02948998	PHASE4	UNKNOWN	Evaluating the Effect of Spironolactone on Hypertrophic Cardiomyopathy
NCT03249272	PHASE4	TERMINATED	Microvascular Dysfunction in Nonischemic Cardiomyopathy: Insights From CMR Assessment of Coronary Flow Reserve
NCT04133532	PHASE4	COMPLETED	Effect of Metoprolol in Post Alcohol Septal Ablation Patients With Hypertrophic Cardiomyopathy
NCT06401343	PHASE4	RECRUITING	Use of SGLT2i in noHCM With HFpEF
NCT07103655	PHASE4	NOT_YET_RECRUITING	The Therapeutic Value of Mavacamten in Hypertrophic Cardiomyopathy With Mid-to-Apical Left Ventricular Obstruction
NCT07600177	PHASE4	RECRUITING	Mavacamten to Aficamten Transition in Patients With Obstructive Hypertrophic Cardiomyopathy
NCT00211796	PHASE4	COMPLETED	Divalproex Sodium ER in Adult Autism
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT00409747	PHASE4	COMPLETED	Minocycline to Treat Childhood Regressive Autism
NCT00576732	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder
NCT00844753	PHASE4	COMPLETED	Atomoxetine, Placebo and Parent Management Training in Autism
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01098383	PHASE4	UNKNOWN	Treatment With Acetyl-Choline Esterase Inhibitors in Children With Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02069977	PHASE4	UNKNOWN	Study to Evaluate the Efficacy and Safety of Aripiprazole
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02199925	PHASE4	UNKNOWN	An Open-Label Study to Evaluate the Efficacy of High-Dose Gammaplex in Children on the Autism Spectrum
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02255565	PHASE4	COMPLETED	Dose Response Effects of Quillivant XR in Children With ADHD and Autism: A Pilot Study
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT00317967	PHASE3	COMPLETED	Study to Determine if Atorvastatin Reduces Size and Stiffness of Muscle in the Left Ventricle of the Heart
NCT00698074	PHASE3	UNKNOWN	Diastolic Ventricular Interaction and the Effects of Biventricular Pacing in Hypertrophic Cardiomyopathy
NCT00821353	PHASE3	COMPLETED	Antiarrhythmic Therapy Versus Catheter Ablation for Atrial Fibrillation in Hypertrophic Cardiomyopathy