ETFB

Summary

ETFB (electron transfer flavoprotein subunit beta, HGNC:3482) is a protein-coding gene on chromosome 19q13.41, encoding Electron transfer flavoprotein subunit beta (P38117). Heterodimeric electron transfer flavoprotein that accepts electrons from several mitochondrial dehydrogenases, including acyl-CoA dehydrogenases, glutaryl-CoA and sarcosine dehydrogenase.

This gene encodes electron-transfer-flavoprotein, beta polypeptide, which shuttles electrons between primary flavoprotein dehydrogenases involved in mitochondrial fatty acid and amino acid catabolism and the membrane-bound electron transfer flavoprotein ubiquinone oxidoreductase. The gene deficiencies have been implicated in type II glutaricaciduria. Alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 2109 — RefSeq curated summary.

At a glance

• Gene–disease (curated): multiple acyl-CoA dehydrogenase deficiency (Definitive, ClinGen)
• Clinical variants (ClinVar): 404 total — 13 pathogenic, 24 likely-pathogenic
• Phenotypes (HPO): 46
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_001985

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3482
Approved symbol	ETFB
Name	electron transfer flavoprotein subunit beta
Location	19q13.41
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000105379
Ensembl biotype	protein_coding
OMIM	130410
Entrez	2109

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 14 protein_coding, 2 retained_intron

ENST00000309244, ENST00000354232, ENST00000593992, ENST00000594361, ENST00000596253, ENST00000903302, ENST00000903303, ENST00000903304, ENST00000903305, ENST00000903306, ENST00000903307, ENST00000903308, ENST00000903309, ENST00000903310, ENST00000922469, ENST00000970335

RefSeq mRNA: 2 — MANE Select: NM_001985 NM_001014763, NM_001985

CCDS: CCDS12828, CCDS33085

Canonical transcript exons

ENST00000309244 — 6 exons

Exon	Start	End
ENSE00000722391	51350329	51350391
ENSE00000722401	51346900	51347058
ENSE00001384271	51366270	51366388
ENSE00003555156	51354150	51354308
ENSE00003687208	51353132	51353290
ENSE00003902357	51345169	51345381

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 99.36.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 47.3650 / max 466.6457, expressed in 1824 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
182388	47.1096	1824
182387	0.2554	124

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	99.36	gold quality
right lobe of liver	UBERON:0001114	99.00	gold quality
heart left ventricle	UBERON:0002084	98.81	gold quality
cardiac ventricle	UBERON:0002082	98.75	gold quality
right atrium auricular region	UBERON:0006631	98.70	gold quality
right adrenal gland	UBERON:0001233	98.51	gold quality
left adrenal gland	UBERON:0001234	98.45	gold quality
right adrenal gland cortex	UBERON:0035827	98.43	gold quality
mucosa of transverse colon	UBERON:0004991	98.41	gold quality
left adrenal gland cortex	UBERON:0035825	98.32	gold quality
cardiac atrium	UBERON:0002081	98.31	gold quality
liver	UBERON:0002107	98.16	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.15	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.14	gold quality
gastrocnemius	UBERON:0001388	98.03	gold quality
heart	UBERON:0000948	98.00	gold quality
putamen	UBERON:0001874	97.90	gold quality
nucleus accumbens	UBERON:0001882	97.88	gold quality
adrenal cortex	UBERON:0001235	97.82	gold quality
heart right ventricle	UBERON:0002080	97.77	gold quality
muscle of leg	UBERON:0001383	97.74	gold quality
mucosa of stomach	UBERON:0001199	97.72	gold quality
cingulate cortex	UBERON:0003027	97.68	gold quality
anterior cingulate cortex	UBERON:0009835	97.68	gold quality
adrenal gland	UBERON:0002369	97.59	gold quality
caudate nucleus	UBERON:0001873	97.57	gold quality
esophagus mucosa	UBERON:0002469	97.42	gold quality
amygdala	UBERON:0001876	97.39	gold quality
adult mammalian kidney	UBERON:0000082	97.33	gold quality
lower esophagus mucosa	UBERON:0035834	97.26	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-5	yes	1023.33
E-HCAD-10	yes	38.44
E-MTAB-10553	yes	29.61
E-MTAB-7303	no	1396.50
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 15)

• non-productive conformation stabilization underpins rapid electron transfer to electron-transferring flavoprotein (PMID:15975918)
• Tissue samples from 16 unrelated patients with ETF deficiency were analysed, two of them harboured mutations in the ETFB gene. (PMID:16510302)
• conformational and stability properties of the disease-causing variant ETFbeta-D128N, and our findings on the effect of flavinylation in modulating protein conformational stability and activity. (PMID:19088074)
• Data established structural hotspots within the ETF fold, and provided a rationale for the prediction of effects of mutations in ETF. (PMID:20674745)
• ETFB participates in the mechanoregulation of fibroblast cell number in collagen gel culture. (PMID:21903359)
• Point mutations in electron-transfer-flavoprotein beta is associated with destabilized conformations and defective protein:protein interactions leading to mitochondrial dysfunction. (PMID:22588007)
• ETFB knockdown can affect TGF-beta-induced tissue remodeling and/or fibrotic processes in vitro. (PMID:23068445)
• Human METTL20 is a mitochondrial lysine methyltransferase that targets ETFbeta and modulates its activity. (PMID:25416781)
• Electron Transfer Flavoprotein Subunit Beta Is a Candidate Endothelial Cell Autoantigen in Behcet’s Disease (PMID:25915519)
• the findings of our present study suggest that ETFbeta plays an important role in renal tubular cell apoptosis during the progression of DN. (PMID:27035869)
• These results suggested that increasing levels of ATP5B and ETFB were associated with worsening renal injury. (PMID:27840937)
• We identified and replicated a novel gene, ETFB, strongly associated with chronic anthracycline-induced cardiotoxicity independently of age at tumor onset and related to anthracycline-mediated mitochondrial dysfunction (PMID:28913729)
• 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)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	etfb	ENSDARG00000009250
mus_musculus	Etfb	ENSMUSG00000004610
rattus_norvegicus	Etfb	ENSRNOG00000017851
drosophila_melanogaster	Etfb	FBGN0039697
caenorhabditis_elegans	F23C8.5	WBGENE00017734

Protein

Protein identifiers

Electron transfer flavoprotein subunit beta — P38117 (reviewed: P38117)

All UniProt accessions (2): P38117, M0QY67

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. Required for normal mitochondrial fatty acid oxidation and normal amino acid metabolism. ETFB binds an AMP molecule that probably has a purely structural role.

Subunit / interactions. Heterodimer composed of ETFA and ETFB. Identified in a complex that contains ETFA, ETFB and ETFRF1. Interacts with ACADM. Interacts with MBTPS1; the interaction stabilizes the ETFA/ETFB heterodimer and promotes FAD binding.

Subcellular location. Mitochondrion matrix.

Tissue specificity. Abundant in liver, heart and skeletal muscle. A weak expression is seen in the brain, placenta, lung, kidney and pancreas.

Post-translational modifications. Methylated. Trimethylation at Lys-200 and Lys-203 may negatively regulate the activity in electron transfer from acyl-CoA dehydrogenases.

Disease relevance. Glutaric aciduria 2B (GA2B) [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.

Domain organisation. The recognition loop recognizes a hydrophobic patch at the surface of interacting dehydrogenases and acts as a static anchor at the interface.

Similarity. Belongs to the ETF beta-subunit/FixA family.

Isoforms (2)

UniProt ID	Names	Canonical?
P38117-1	1	yes
P38117-2	2

RefSeq proteins (2): NP_001014763, NP_001976* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000049	ET-Flavoprotein_bsu_CS	Conserved_site
IPR012255	ETF_b	Family
IPR014729	Rossmann-like_a/b/a_fold	Homologous_superfamily
IPR014730	ETF_a/b_N	Domain
IPR033948	ETF_beta_N	Domain

Pfam: PF01012

UniProt features (54 total): strand 13, modified residue 12, helix 9, mutagenesis site 6, binding site 4, sequence variant 3, turn 2, initiator methionine 1, chain 1, splice variant 1, region of interest 1, sequence conflict 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-P38117-F1	96.19	0.96

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 (4): 9; 39–42; 66; 123–134

Post-translational modifications (12): 200, 203, 210, 210, 223, 226, 238, 248, 248, 2, 200, 200

Mutagenesis-validated functional residues (6):

Position	Phenotype
165	drastically increases interprotein electron transfer rates.
195	severely impaired in complex formation with acadm.
200–203	does not abolish electron transfer activity. abolishes sensitivity to inhibition by lysine methyltransferase etfbkmt.
200–202	does not abolish methylation by etfbkmt.
200	does not abolish electron transfer activity. decreases sensitivity to inhibition by lysine methyltransferase etfbkmt.
203	does not abolish electron transfer activity. decreases sensitivity to inhibition by lysine methyltransferase etfbkmt.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-611105	Respiratory electron transport
R-HSA-8876725	Protein methylation

MSigDB gene sets: 344 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, GOBP_LIPID_MODIFICATION, MODULE_93, MODULE_52, GOBP_FATTY_ACID_CATABOLIC_PROCESS, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, MYOGENIN_Q6, MODULE_151, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_FATTY_ACID_BETA_OXIDATION_USING_ACYL_COA_DEHYDROGENASE, GOLDRATH_ANTIGEN_RESPONSE, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS

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 (2): electron transfer activity (GO:0009055), 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-2 pathways:

Category	Pathways
Aerobic respiration and respiratory electron transport	1
Post-translational protein modification	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
binding	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1
protein-containing complex	1

Protein interactions and networks

STRING

2224 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ETFB	ETFA	P13804	999
ETFB	ETFDH	Q16134	996
ETFB	ACADS	P16219	750
ETFB	FLAD1	Q8NFF5	718
ETFB	LIM2	P55344	656
ETFB	ACADVL	P49748	571
ETFB	HADHA	P40939	548
ETFB	GCDH	Q92947	541
ETFB	HADHB	P55084	540
ETFB	ACAA2	P42765	538
ETFB	SUCLG1	P53597	535
ETFB	NDUFV1	P49821	528
ETFB	ACADM	P11310	520
ETFB	SLC52A1	Q9NWF4	516
ETFB	SLC25A32	Q9H2D1	506
ETFB	COX5A	P20674	506

IntAct

124 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
PRKACB	PRKAR1A	psi-mi:“MI:0914”(association)	0.790
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
HLA-A	TAPBP	psi-mi:“MI:0915”(physical association)	0.690
ETFB	ETFRF1	psi-mi:“MI:0915”(physical association)	0.660
ETFRF1	NDUFAB1	psi-mi:“MI:0914”(association)	0.640
RAP1GDS1	DIRAS1	psi-mi:“MI:0914”(association)	0.640
NDUFAB1	GLDC	psi-mi:“MI:0914”(association)	0.530
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
HSCB	NDUFS8	psi-mi:“MI:0914”(association)	0.460
HLA-A	C	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (251): ETFB (Affinity Capture-MS), ETFB (Affinity Capture-MS), ETFA (Co-fractionation), ETFB (Co-fractionation), ETFB (Co-fractionation), ETFB (Co-fractionation), ETFB (Co-fractionation), GPX4 (Co-fractionation), PITPNB (Co-fractionation), ETFB (Affinity Capture-MS), ETFB (Proximity Label-MS), ETFB (Affinity Capture-MS), ETFB (Affinity Capture-MS), ETFB (Affinity Capture-MS), ETFB (Affinity Capture-MS)

ESM2 similar proteins: A0B8M6, A0B922, A0LLA3, A2XQV4, A5CT01, A7I6S6, A8MAJ1, A9GBF1, B0RDZ5, B8JAE9, G3KIM7, H6LBB0, H6LGM7, O33095, P09818, P09819, P10449, P26482, P26483, P38117, P38975, P42940, P53570, P53574, P53575, P53576, P53577, P64098, P97089, P9WNG6, P9WNG7, Q05559, Q0AZ34, Q0W6K3, Q2IIB1, Q2TBV3, Q53209, Q53210, Q54YZ4, Q5RFK0

Diamond homologs: A2XQV4, H6LGM7, O85691, P26482, P38117, P38975, P42940, P52040, P53570, P53575, P53577, P64098, P94550, P97089, P9WNG6, P9WNG7, Q05559, Q0AZ34, Q2TBV3, Q53210, Q54YZ4, Q5RFK0, Q68FU3, Q6UAQ8, Q7F9U3, Q9DCW4, Q9HZP6, Q9LSW8, Q9UTH2, A7ZHD4, A7ZVZ3, A9MYK3, B1IRD5, B1LFX5, B1XBG6, B4T6K2, B5BL59, B5F756, B5FHH0, B5RGA8

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
ETFB	“form complex”	ETF	binding
ETFBKMT	“down-regulates activity”	ETFB	methylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 126 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 degradation	8	11.7×	2e-04
Mitochondrial protein import	5	10.8×	6e-03
Complex I biogenesis	5	10.6×	6e-03
Respiratory electron transport	7	8.5×	2e-03
Aerobic respiration and respiratory electron transport	6	6.8×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial electron transport, NADH to ubiquinone	5	16.9×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	13
Likely pathogenic	24
Uncertain significance	106
Likely benign	184
Benign	43

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1322834	NM_001985.3(ETFB):c.284_293del (p.Glu95fs)	Pathogenic
1416429	NM_001985.3(ETFB):c.426_427insTTTTTTTTTTTTTTTTTTTTNNNNNNNNNNTCTCCTGACCTCTAGATCCACCCGCCTCGGCCTCCCCAAGTGCTGGGATTACAGGCGTGAGCCACCGCGCCCGGCCGACAGCTGGATTTCTT (p.Asp143delinsPhePhePhePhePhePheXaaXaaXaaXaaSerProAspLeuTer)	Pathogenic
16717	NM_001985.3(ETFB):c.597+1G>C	Pathogenic
2032940	NM_001985.3(ETFB):c.454C>T (p.Gln152Ter)	Pathogenic
2812844	NM_001985.3(ETFB):c.386dup (p.Asp129fs)	Pathogenic
2848141	NM_001985.3(ETFB):c.362del (p.Leu121fs)	Pathogenic
3248430	NC_000019.9:g.(?51869504)(51869580_?)del	Pathogenic
3248431	NC_000019.9:g.(?51850134)(51869580_?)del	Pathogenic
3248432	NC_000019.9:g.(?51848465)(51850332_?)del	Pathogenic
3723665	NM_001985.3(ETFB):c.81del (p.Gly28fs)	Pathogenic
4769409	NM_001985.3(ETFB):c.368del (p.Gly123fs)	Pathogenic
59117	GRCh38/hg38 19q13.33-13.43(chr19:47929575-58572206)x3	Pathogenic
800736	Single allele	Pathogenic
1804737	NM_001985.3(ETFB):c.375+1G>T	Likely pathogenic
1805746	NM_001985.3(ETFB):c.136del (p.Val46fs)	Likely pathogenic
2034613	NM_001985.3(ETFB):c.341_375+154del	Likely pathogenic
203701	NM_001985.3(ETFB):c.160G>A (p.Glu54Lys)	Likely pathogenic
203704	NM_001985.3(ETFB):c.236T>A (p.Leu79Gln)	Likely pathogenic
2074298	NM_001985.3(ETFB):c.375+1G>A	Likely pathogenic
2138318	NM_001985.3(ETFB):c.375G>C (p.Gln125His)	Likely pathogenic
2675089	NM_001985.3(ETFB):c.32dup (p.Arg12fs)	Likely pathogenic
2675090	NM_001985.3(ETFB):c.163A>T (p.Lys55Ter)	Likely pathogenic
2675093	NM_001985.3(ETFB):c.375+1G>C	Likely pathogenic
2675094	NM_001985.3(ETFB):c.671_672del (p.Val224fs)	Likely pathogenic
2675095	NM_001985.3(ETFB):c.208del (p.Gln70fs)	Likely pathogenic
2675098	NM_001985.3(ETFB):c.94del (p.Asp32fs)	Likely pathogenic
2776661	NM_001985.3(ETFB):c.216+1G>C	Likely pathogenic
2784144	NM_001985.3(ETFB):c.439-1G>A	Likely pathogenic
3241420	NM_001985.3(ETFB):c.341_342delinsT (p.Lys114fs)	Likely pathogenic
3241421	NM_001985.3(ETFB):c.376-2A>C	Likely pathogenic

SpliceAI

826 predictions. Top by Δscore:

Variant	Effect	Δscore
19:51345380:TTCTG:T	acceptor_loss	1.0000
19:51345381:TCTGC:T	acceptor_loss	1.0000
19:51346894:GCTCA:G	donor_loss	1.0000
19:51346895:CTCAC:C	donor_loss	1.0000
19:51346896:TCA:T	donor_loss	1.0000
19:51346897:CAC:C	donor_loss	1.0000
19:51346898:A:AC	donor_gain	1.0000
19:51346898:A:T	donor_loss	1.0000
19:51346898:AC:A	donor_gain	1.0000
19:51346899:C:A	donor_loss	1.0000
19:51346899:C:CC	donor_gain	1.0000
19:51346899:CC:C	donor_gain	1.0000
19:51346899:CCATG:C	donor_gain	1.0000
19:51347054:GTGCC:G	acceptor_gain	1.0000
19:51347055:TGCC:T	acceptor_gain	1.0000
19:51347056:GCCC:G	acceptor_loss	1.0000
19:51347057:CC:C	acceptor_gain	1.0000
19:51347058:CC:C	acceptor_gain	1.0000
19:51347059:C:CC	acceptor_gain	1.0000
19:51347070:CAG:C	acceptor_gain	1.0000
19:51347071:A:T	acceptor_gain	1.0000
19:51347072:G:C	acceptor_gain	1.0000
19:51347072:G:GC	acceptor_gain	1.0000
19:51354146:TCA:T	donor_loss	1.0000
19:51354147:CA:C	donor_loss	1.0000
19:51354147:CACCT:C	donor_loss	1.0000
19:51354148:A:C	donor_loss	1.0000
19:51354149:C:CA	donor_loss	1.0000
19:51354149:CCT:C	donor_loss	1.0000
19:51354187:T:TA	donor_gain	1.0000

AlphaMissense

1639 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:51346913:A:T	L195Q	0.999
19:51353268:G:T	A80D	0.999
19:51354249:G:C	N39K	0.999
19:51354249:G:T	N39K	0.999
19:51345373:C:A	K202N	0.998
19:51345373:C:G	K202N	0.998
19:51346904:A:T	I198N	0.998
19:51346919:G:T	A193D	0.998
19:51354171:G:C	S65R	0.998
19:51354171:G:T	S65R	0.998
19:51354173:T:G	S65R	0.998
19:51354243:G:C	F41L	0.998
19:51354243:G:T	F41L	0.998
19:51354245:A:G	F41L	0.998
19:51345377:G:T	A201D	0.997
19:51345378:C:G	A201P	0.997
19:51346904:A:C	I198S	0.997
19:51346904:A:G	I198T	0.997
19:51347006:C:G	R164P	0.997
19:51353136:T:A	K124I	0.997
19:51353274:G:T	A78D	0.997
19:51346913:A:C	L195R	0.996
19:51346913:A:G	L195P	0.996
19:51350351:G:T	A139D	0.996
19:51353135:T:A	K124N	0.996
19:51353135:T:G	K124N	0.996
19:51353139:C:A	G123V	0.996
19:51354221:C:G	A49P	0.996
19:51354240:A:C	C42W	0.996
19:51354241:C:A	C42F	0.996

dbSNP variants (sampled 300 via entrez): RS1000074409 (19:51351452 T>C), RS1000090873 (19:51348100 T>G), RS1000147798 (19:51351187 G>A), RS1000164571 (19:51361340 G>A,C), RS1000451099 (19:51350454 C>T), RS1000951091 (19:51357156 C>T), RS1001001839 (19:51357351 G>A), RS1001149849 (19:51352549 C>T), RS1001328507 (19:51359376 A>C), RS1001506534 (19:51356337 T>C), RS1001510420 (19:51349804 G>A), RS1001613107 (19:51348645 A>G), RS1001728592 (19:51361778 C>A), RS1001955425 (19:51356648 C>T), RS1002017690 (19:51348244 T>C)

Disease associations

OMIM: gene MIM:130410 | disease phenotypes: MIM:231680

GenCC curated gene-disease

Disease	Classification	Inheritance
multiple acyl-CoA dehydrogenase deficiency	Definitive	Autosomal recessive

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 (4): multiple acyl-CoA dehydrogenase deficiency (MONDO:0009282), glutaric acidemia IIc (MONDO:0700076), glutaric acidemia IIb (MONDO:0700074), chronic kidney disease (MONDO:0005300)

Orphanet (1): Multiple acyl-CoA dehydrogenase deficiency (Orphanet:26791)

HPO phenotypes

46 total (30 of 46 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000078	Abnormality of the genital system
HP:0000113	Polycystic kidney dysplasia
HP:0000114	Proximal tubulopathy
HP:0000256	Macrocephaly
HP:0000260	Wide anterior fontanel
HP:0000348	High forehead
HP:0000377	Abnormal pinna morphology
HP:0000506	Telecanthus
HP:0000519	Developmental cataract
HP:0000803	Renal cortical cysts
HP:0000952	Jaundice
HP:0001252	Hypotonia
HP:0001302	Pachygyria
HP:0001324	Muscle weakness
HP:0001325	Hypoglycemic coma
HP:0001397	Hepatic steatosis
HP:0001639	Hypertrophic cardiomyopathy
HP:0001733	Pancreatitis
HP:0001941	Acidosis
HP:0001943	Hypoglycemia
HP:0001999	Abnormal facial shape
HP:0002013	Vomiting
HP:0002018	Nausea
HP:0002089	Pulmonary hypoplasia
HP:0002098	Respiratory distress
HP:0002171	Gliosis
HP:0002240	Hepatomegaly
HP:0002254	Intermittent diarrhea
HP:0002614	Hepatic periportal necrosis

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D007676	Kidney Failure, Chronic	C12.050.351.968.419.780.750.500; C12.200.777.419.780.750.500; C12.950.419.780.750.500; C23.550.291.500.906.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105744 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 2,167 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL2105728	CRENOLANIB	3	2,167

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs79338777	ETFB		0.00	0

ChEMBL bioactivities

1 potent at pChembl≥5 of 3 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.92	Kd	12	nM	CRENOLANIB

PubChem BioAssay actives

1 with measured affinity, of 182 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
1-[2-[5-[(3-methyloxetan-3-yl)methoxy]benzimidazol-1-yl]quinolin-8-yl]piperidin-4-amine	1424999: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0120	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, affects reaction, affects expression, decreases expression	5
Benzo(a)pyrene	affects methylation, decreases expression, increases expression	5
Acetaminophen	affects cotreatment, decreases expression	4
Tetrachlorodibenzodioxin	increases expression	4
Arsenic	affects methylation, decreases expression, increases abundance	2
Doxorubicin	decreases expression, affects response to substance	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
Cyclosporine	decreases expression	2
Cadmium Chloride	increases abundance, increases expression	2
tert-Butylhydroperoxide	decreases expression, increases methylation	2
aristolochic acid I	increases expression	1
bisphenol F	increases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
sodium arsenate	decreases expression, increases abundance	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression, increases expression	1
decabromobiphenyl ether	increases expression	1
arsenite	affects binding, increases reaction	1
sodium arsenite	increases expression	1
cobaltous chloride	decreases expression	1
tetrabromobisphenol A	decreases expression	1
perfluorooctanoic acid	increases expression	1
sulindac sulfide	decreases expression	1
pinosylvin	increases expression	1
4-hydroxy-equilenin	decreases expression	1
azoxystrobin	increases expression	1
CGP 52608	affects binding, increases reaction	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
bisphenol B	increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3991712	Binding	Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by ma	The target landscape of clinical kinase drugs. — Science

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SM50	HAP1 ETFB (-) 1	Cancer cell line	Male
CVCL_SM51	HAP1 ETFB (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00073710	PHASE4	COMPLETED	Study to Evaluate the Effects of Zemplar Injection and Calcijex on Intestinal Absorption of Calcium
NCT00125593	PHASE4	COMPLETED	Study of Heart and Renal Protection
NCT00132431	PHASE4	COMPLETED	START: Sensipar Treatment Algorithm to Reach K/DOQI Targets in Chronic Kidney Disease Subjects With Secondary Hyperparathyroidism
NCT00155246	PHASE4	COMPLETED	Efficacy of Pentoxifylline on Chronic Kidney Disease
NCT00175149	PHASE4	TERMINATED	Active Vitamin D Effect on Left Ventricular Hypertrophy
NCT00184769	PHASE4	COMPLETED	Growth Hormone Treatment in Infants Aged 1 to 2 Years With Chronic Renal Insufficiency (CRI) and Growth Retardation.
NCT00190580	PHASE4	COMPLETED	Kanagawa Valsartan Trial (KVT): Effects of Valsartan on Renal and Cardiovascular Disease
NCT00194961	PHASE4	TERMINATED	Effect of Growth Hormone on Leptin, Cytokines and Body Composition of Children With Growth Failure Due to Chronic Kidney Disease
NCT00239642	PHASE4	COMPLETED	Safety and Efficacy of Iron Sucrose in Children
NCT00324571	PHASE4	COMPLETED	Dialysis Clinical Outcomes Revisited (DCOR) Trial
NCT00364884	PHASE4	UNKNOWN	Keto-/Amino Acid Supplemented Low Protein Diet in Patients With Chronic Kidney Disease
NCT00368901	PHASE4	COMPLETED	STAAR-2 Clinical Study
NCT00369733	PHASE4	COMPLETED	STAAR-3 Clinical Study
NCT00369772	PHASE4	COMPLETED	STAAR-1 Clinical Study
NCT00379899	PHASE4	COMPLETED	ADVANCE: Study to Evaluate Cinacalcet Plus Low Dose Vitamin D on Vascular Calcification in Subjects With Chronic Kidney Disease Receiving Hemodialysis
NCT00384618	PHASE4	TERMINATED	Anti-Oxidant Therapy In Chronic Renal Insufficiency (ATIC) Study
NCT00478543	PHASE4	COMPLETED	Loop Diuretics in Chronic Kidney Disease
NCT00632125	PHASE4	COMPLETED	Post-authorization Safety Study in CKD Subjects Receiving HX575 i.v.
NCT00644046	PHASE4	COMPLETED	Chronic Kidney Disease Prevention of An-Lo District, Keelung
NCT00719316	PHASE4	UNKNOWN	Aliskiren and Muscle Sympathetic Nerve Activity
NCT00725517	PHASE4	COMPLETED	Efficacy and Safety of a 7.5% Icodextrin Peritoneal Dialysis Solution in Once-Daily Long Dwell Exchange
NCT00741585	PHASE4	COMPLETED	Prognostic Value of the Circadian Pattern of Ambulatory Blood Pressure for Multiple Risk Assessment
NCT00749736	PHASE4	COMPLETED	The Role of Vitamin D in Immune Function in Patients With Chronic Kidney Disease (CKD) Stages 3 and 4.
NCT00752102	PHASE4	COMPLETED	Vitamin D and Coronary Calcification Study
NCT00756145	PHASE4	COMPLETED	The Use of Low Molecular Weight Heparin in Hemodiafiltration
NCT00768638	PHASE4	COMPLETED	Study of Atorvastatin Dose Dependent Reduction of Proteinuria
NCT00786136	PHASE4	COMPLETED	Rosuvastatin Prevent Contrast Induced Acute Kidney Injury in Patients With Diabetes
NCT00803712	PHASE4	COMPLETED	20070360 Incident Dialysis
NCT00812123	PHASE4	COMPLETED	Calcineurin Free Immunosuppression in Renal Transplant Recipients
NCT00823303	PHASE4	COMPLETED	Paricalcitol Versus Calcitriol for Efficacy and Safety in Stage 3/4 Chronic Kidney Disease (CKD) With Secondary Hyperparathyroidism (SHPT)
NCT00830037	PHASE4	TERMINATED	A Clinical Trial of Oral Versus IV Iron in Patients With Chronic Kidney Disease
NCT00852969	PHASE4	COMPLETED	Niacin and Endothelial Function in Early CKD
NCT00858299	PHASE4	UNKNOWN	The Change of Urinary Angiotensinogen Excretion After Valsartan Treatment in Patients With Persistent Proteinuria
NCT00860431	PHASE4	COMPLETED	Kremezin Study Against Renal Disease Progression in Korea
NCT00882401	PHASE4	COMPLETED	Vitamin D, Chronic Kidney Disease (CKD) and the Microcirculation
NCT00889629	PHASE4	COMPLETED	Pilot Study Evaluating Doxercalciferol Replacement Therapy in Kidney Transplant Recipients
NCT00892892	PHASE4	WITHDRAWN	Sympathetic Nerve Activity in Renal Failure
NCT00893425	PHASE4	COMPLETED	Effect of Renin Angiotensin System Blockade on the Fas Antigen (CD95) and Asymmetric Dimethylarginine (ADMA) Levels in Type-2 Diabetic Patients With Proteinuria
NCT00908310	PHASE4	COMPLETED	Post-marketing Safety Study in Patients With Moderate Renal Insufficiency Who Receive Omniscan for Contrast-enhanced Magnetic Resonance Imaging (MRI)
NCT00958451	PHASE4	COMPLETED	Vitamin D Deficiency in Chronic Kidney Disease (CKD) Patients