ETFBKMT

Summary

ETFBKMT (electron transfer flavoprotein subunit beta lysine methyltransferase, HGNC:28739) is a protein-coding gene on chromosome 12p11.21, encoding Electron transfer flavoprotein beta subunit lysine methyltransferase (Q8IXQ9). Protein-lysine methyltransferase that selectively trimethylates the flavoprotein ETFB in mitochondria.

Enables heat shock protein binding activity and protein-lysine N-methyltransferase activity. Involved in negative regulation of fatty acid beta-oxidation using acyl-CoA dehydrogenase. Located in mitochondrial matrix. Part of protein-containing complex.

Source: NCBI Gene 254013 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 12 total
• MANE Select transcript: NM_001135863

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28739
Approved symbol	ETFBKMT
Name	electron transfer flavoprotein subunit beta lysine methyltransferase
Location	12p11.21
Locus type	gene with protein product
Status	Approved
Aliases	DKFZp451L235, MGC50559
Ensembl gene	ENSG00000139160
Ensembl biotype	protein_coding
OMIM	615256
Entrez	254013

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 13 protein_coding

ENST00000357721, ENST00000395763, ENST00000412352, ENST00000538391, ENST00000538463, ENST00000539633, ENST00000870608, ENST00000870609, ENST00000870610, ENST00000870611, ENST00000870612, ENST00000920053, ENST00000961947

RefSeq mRNA: 3 — MANE Select: NM_001135863 NM_001135863, NM_001135864, NM_173802

CCDS: CCDS8724

Canonical transcript exons

ENST00000357721 — 4 exons

Exon	Start	End
ENSE00000936720	31666087	31666217
ENSE00001301281	31661841	31662267
ENSE00001405269	31667647	31673114
ENSE00001412570	31659688	31659789

Expression profiles

Bgee: expression breadth ubiquitous, 180 present calls, max score 95.99.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 1.6180 / max 48.3036, expressed in 1042 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
124934	1.0716	787
124935	0.5464	302

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	95.99	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.49	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.67	gold quality
muscle of leg	UBERON:0001383	76.42	gold quality
gastrocnemius	UBERON:0001388	76.26	gold quality
oviduct epithelium	UBERON:0004804	75.67	gold quality
islet of Langerhans	UBERON:0000006	75.39	gold quality
calcaneal tendon	UBERON:0003701	75.19	gold quality
stromal cell of endometrium	CL:0002255	75.05	gold quality
hindlimb stylopod muscle	UBERON:0004252	74.82	gold quality
right lobe of liver	UBERON:0001114	74.71	gold quality
right adrenal gland	UBERON:0001233	74.31	gold quality
right adrenal gland cortex	UBERON:0035827	74.23	gold quality
left adrenal gland	UBERON:0001234	73.96	gold quality
left adrenal gland cortex	UBERON:0035825	73.43	gold quality
adrenal tissue	UBERON:0018303	73.08	gold quality
adrenal gland	UBERON:0002369	72.83	gold quality
smooth muscle tissue	UBERON:0001135	72.77	gold quality
cortical plate	UBERON:0005343	72.56	gold quality
pancreas	UBERON:0001264	72.00	gold quality
body of pancreas	UBERON:0001150	71.46	gold quality
adrenal cortex	UBERON:0001235	71.28	gold quality
heart left ventricle	UBERON:0002084	70.92	gold quality
medial globus pallidus	UBERON:0002477	70.92	gold quality
liver	UBERON:0002107	70.76	gold quality
gall bladder	UBERON:0002110	70.63	gold quality
cerebellar hemisphere	UBERON:0002245	70.53	gold quality
Brodmann (1909) area 9	UBERON:0013540	70.53	gold quality
cerebellar cortex	UBERON:0002129	70.49	gold quality
fallopian tube	UBERON:0003889	70.36	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.63

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

81 targeting ETFBKMT, 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-3613-3P	100.00	76.36	7965
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502

Literature-anchored findings (GeneRIF, showing 4)

• The METTL20 protein is here suggested to be a protein methyltransferase, as it is shown to belong to a family of 10 human methyltransferases, some of which are shown to have lysine specific protein methyltransferase activity. (PMID:22948820)
• Tagged METTL20 expressed in HEK293T cells specifically associates with the ETF and promotes the trimethylation of ETFbeta lysine residues 199 and 202 (PMID:25023281)
• Human METTL20 is a mitochondrial lysine methyltransferase that targets ETFbeta and modulates its activity. (PMID:25416781)
• These results further indicate that METTL20-mediated protein methylation is not essential in humans but more likely modulates energy production during fasting or under other metabolic conditions where beta-oxidation is up-regulated. (PMID:29352221)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Etfbkmt	ENSMUSG00000039958
rattus_norvegicus	Etfbkmt	ENSRNOG00000036918

Paralogs (2): HEMK1 (ENSG00000114735), HEMK2 (ENSG00000156239)

Protein

Protein identifiers

Electron transfer flavoprotein beta subunit lysine methyltransferase — Q8IXQ9 (reviewed: Q8IXQ9)

Alternative names: ETFB lysine methyltransferase, Protein N-lysine methyltransferase METTL20

All UniProt accessions (3): Q8IXQ9, F5H481, G5EA40

UniProt curated annotations — full annotation on UniProt →

Function. Protein-lysine methyltransferase that selectively trimethylates the flavoprotein ETFB in mitochondria. Thereby, may negatively regulate the function of ETFB in electron transfer from Acyl-CoA dehydrogenases to the main respiratory chain.

Subunit / interactions. Interacts with HSPD1; this protein may possibly be a methylation substrate.

Subcellular location. Cytoplasm. Mitochondrion matrix.

Similarity. Belongs to the methyltransferase superfamily. ETFBKMT family.

RefSeq proteins (3): NP_001129335, NP_001129336, NP_776163 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR029063	SAM-dependent_MTases_sf	Homologous_superfamily
IPR050078	Ribosomal_L11_MeTrfase_PrmA	Family

Pfam: PF06325

Catalyzed reactions (Rhea), 1 shown:

• L-lysyl-[protein] + 3 S-adenosyl-L-methionine = N(6),N(6),N(6)-trimethyl-L-lysyl-[protein] + 3 S-adenosyl-L-homocysteine + 3 H(+) (RHEA:54192)

UniProt features (3 total): transit peptide 1, chain 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IXQ9-F1	85.81	0.78

Functional residue map

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

Mutagenesis-validated functional residues (1):

Position	Phenotype
121	loss of lysine methyltransferase activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8876725	Protein methylation

MSigDB gene sets: 135 (showing top): GOBP_LIPID_MODIFICATION, GOBP_FATTY_ACID_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_LIPID_METABOLIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_KETONE_METABOLIC_PROCESS, GOBP_FATTY_ACID_BETA_OXIDATION_USING_ACYL_COA_DEHYDROGENASE, GOBP_REGULATION_OF_FATTY_ACID_METABOLIC_PROCESS, chr12p11, GOBP_REGULATION_OF_LIPID_METABOLIC_PROCESS, UEDA_PERIFERAL_CLOCK, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_REGULATION_OF_KETONE_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, GOBP_LIPID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS

GO Biological Process (2): methylation (GO:0032259), obsolete negative regulation of fatty acid beta-oxidation using acyl-CoA dehydrogenase (GO:1904736)

GO Molecular Function (4): protein-lysine N-methyltransferase activity (GO:0016279), heat shock protein binding (GO:0031072), methyltransferase activity (GO:0008168), transferase activity (GO:0016740)

GO Cellular Component (4): cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
metabolic process	1
protein methyltransferase activity	1
lysine N-methyltransferase activity	1
protein binding	1
transferase activity, transferring one-carbon groups	1
catalytic activity	1
intracellular anatomical structure	1
cellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1
cellular_component	1

Protein interactions and networks

STRING

546 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ETFBKMT	METTL22	Q9BUU2	796
ETFBKMT	EEF1AKMT2	Q5JPI9	723
ETFBKMT	METTL21A	Q8WXB1	716
ETFBKMT	VCPKMT	Q9H867	696
ETFBKMT	METTL18	O95568	687
ETFBKMT	CAMKMT	Q7Z624	661
ETFBKMT	KIN	O60870	656
ETFBKMT	EEF2KMT	Q96G04	651
ETFBKMT	METTL21C	Q5VZV1	648
ETFBKMT	EEF1AKMT3	Q96AZ1	628
ETFBKMT	EEF1AKMT1	Q8WVE0	620
ETFBKMT	METTL23	Q86XA0	619
ETFBKMT	CSKMT	A8MUP2	609
ETFBKMT	ANTKMT	Q9BQD7	469
ETFBKMT	GRWD1	Q9BQ67	411
ETFBKMT	ETFB	P38117	411

IntAct

4 interactions, top by confidence:

A	B	Type	Score
ETFBKMT	HSPD1	psi-mi:“MI:0914”(association)	0.530
ETFBKMT	CLPX	psi-mi:“MI:0914”(association)	0.350
ETFBKMT	NR2F6	psi-mi:“MI:0914”(association)	0.350

BioGRID (36): HSPD1 (Affinity Capture-MS), GLS (Affinity Capture-MS), CLPX (Affinity Capture-MS), SELO (Affinity Capture-MS), SELO (Affinity Capture-MS), HSPD1 (Affinity Capture-MS), CLPX (Affinity Capture-MS), METTL20 (Two-hybrid), METTL20 (Synthetic Lethality), HSPD1 (Affinity Capture-MS), SELO (Affinity Capture-MS), ADK (Affinity Capture-MS), DARS2 (Affinity Capture-MS), NR2F6 (Affinity Capture-MS), ACSF3 (Affinity Capture-MS)

ESM2 similar proteins: A1L251, A3KP85, A3KPF2, A7SLX5, A8XFF4, B0X4N1, B3MF31, B4MNL1, B6JWC1, B8NR70, B9FK36, F4I1L3, F4JNX3, O01503, O13926, O59713, O60157, O94710, P0CI62, P34254, P40389, P41888, P49958, P87241, Q00868, Q09509, Q10170, Q38970, Q42523, Q42777, Q4V7W8, Q6C3P4, Q6GPQ5, Q6GQ37, Q6P7Q0, Q755C1, Q75AW4, Q75B12, Q7QIL2, Q7YTB0

Diamond homologs: A3KP85, A3M6R7, A6VCV6, A9KKT8, B0V7H8, B0VLL0, B3E5Z5, B7H0I7, B7IC17, B7V1R2, C1DLJ6, O01503, Q02FH0, Q4V7W8, Q6F9P9, Q6P7Q0, Q7VAM5, Q7W3W2, Q7WF92, Q80ZM3, Q87KU2, Q8IXQ9, Q9HUW3, A5IHD3, A8FFD0, B5E9X4, B7GKD0, Q5WZ79, Q5X7S8, Q5ZYB1, Q8EPW5, Q9KV64, A0RIT1, A4IR29, A4XQ64, A7Z6V9, B2TM01, B2V2I9, B3WEN7, B7HCT8

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
ETFBKMT	“down-regulates activity”	ETFB	methylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	1
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

938 predictions. Top by Δscore:

Variant	Effect	Δscore
12:31666082:TTTA:T	acceptor_loss	1.0000
12:31666084:TAG:T	acceptor_loss	1.0000
12:31666175:A:G	donor_gain	1.0000
12:31666213:CCCTA:C	donor_gain	1.0000
12:31666214:CCTA:C	donor_gain	1.0000
12:31666215:CTA:C	donor_gain	1.0000
12:31666215:CTAGT:C	donor_loss	1.0000
12:31666216:TA:T	donor_gain	1.0000
12:31666216:TAG:T	donor_loss	1.0000
12:31666217:AGT:A	donor_loss	1.0000
12:31666218:G:GG	donor_gain	1.0000
12:31666218:GTAA:G	donor_loss	1.0000
12:31666219:T:G	donor_loss	1.0000
12:31666223:G:GT	donor_gain	1.0000
12:31667645:A:AG	acceptor_gain	1.0000
12:31667646:G:GA	acceptor_gain	1.0000
12:31666085:A:AG	acceptor_gain	0.9900
12:31666086:G:GG	acceptor_gain	0.9900
12:31666086:GGT:G	acceptor_gain	0.9900
12:31666170:C:G	donor_gain	0.9900
12:31667641:TTTAA:T	acceptor_loss	0.9900
12:31667642:TTAA:T	acceptor_loss	0.9900
12:31667643:TAAGT:T	acceptor_loss	0.9900
12:31667644:A:AG	acceptor_gain	0.9900
12:31667644:AAG:A	acceptor_loss	0.9900
12:31667644:AAGTT:A	acceptor_gain	0.9900
12:31667645:A:T	acceptor_loss	0.9900
12:31667646:G:A	acceptor_loss	0.9900
12:31667708:A:AG	acceptor_gain	0.9900
12:31672374:TGAT:T	acceptor_gain	0.9900

AlphaMissense

1724 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:31666142:A:C	S124R	0.984
12:31666144:T:A	S124R	0.984
12:31666144:T:G	S124R	0.984
12:31667964:A:C	S255R	0.978
12:31667966:C:A	S255R	0.978
12:31667966:C:G	S255R	0.978
12:31667672:T:A	N157K	0.975
12:31667672:T:G	N157K	0.975
12:31666167:C:A	A132D	0.973
12:31662230:T:A	W93R	0.969
12:31662230:T:C	W93R	0.969
12:31667764:A:T	D188V	0.968
12:31666170:C:A	A133D	0.962
12:31667764:A:C	D188A	0.962
12:31667765:T:A	D188E	0.961
12:31667765:T:G	D188E	0.961
12:31662232:G:C	W93C	0.959
12:31662232:G:T	W93C	0.959
12:31666148:T:C	C126R	0.956
12:31666169:G:C	A133P	0.954
12:31662159:T:C	L69S	0.953
12:31666200:C:A	A143D	0.953
12:31667809:T:C	L203P	0.951
12:31662244:G:C	W97C	0.949
12:31662244:G:T	W97C	0.949
12:31666206:A:C	D145A	0.948
12:31666128:T:A	V119E	0.947
12:31666161:C:A	A130D	0.946
12:31662153:T:C	I67T	0.945
12:31662162:G:C	R70P	0.944

dbSNP variants (sampled 300 via entrez): RS1000029996 (12:31669764 G>A), RS1000066970 (12:31649091 A>G), RS1000145513 (12:31654318 G>A), RS1000228265 (12:31650473 TA>T), RS1000324247 (12:31656885 C>G,T), RS1000666135 (12:31650622 C>A), RS1000700972 (12:31655714 T>C), RS1000912519 (12:31662935 G>A), RS1001032660 (12:31671731 C>T), RS1001178401 (12:31662728 T>C), RS1001225408 (12:31650381 C>T), RS1001259197 (12:31670373 T>C), RS1001345166 (12:31663293 A>G), RS1001345803 (12:31655820 G>C), RS1001472766 (12:31663695 G>A)

Disease associations

OMIM: gene MIM:615256 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006088_62	Familial squamous cell lung carcinoma	8.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006953	family history of lung cancer

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	3
Benzo(a)pyrene	increases methylation, decreases expression	2
sodium arsenite	affects methylation	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
perfluoro-n-nonanoic acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	decreases methylation	1
Acetaminophen	decreases expression	1
Cisplatin	increases expression	1
Nickel	decreases expression	1
Phenylmercuric Acetate	decreases expression, affects cotreatment	1
Cyclosporine	increases expression	1
Aflatoxin B1	increases methylation	1
Okadaic Acid	decreases expression	1
Particulate Matter	decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_XQ44	HAP1 METTL20 (-) 1	Cancer cell line	Male
CVCL_XQ45	HAP1 METTL20 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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