TSFM

Summary

TSFM (Ts translation elongation factor, mitochondrial, HGNC:12367) is a protein-coding gene on chromosome 12q14.1, encoding Elongation factor Ts, mitochondrial (P43897). Associates with the EF-Tu.GDP complex and induces the exchange of GDP to GTP. It is a selective cancer dependency (DepMap: 30.5% of cell lines).

This gene encodes a mitochondrial translation elongation factor. The encoded protein is an enzyme that catalyzes the exchange of guanine nucleotides on the translation elongation factor Tu during the elongation step of mitchondrial protein translation. Mutations in this gene are associated with combined oxidative phosphorylation deficiency-3 syndrome. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 10102 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 579 total — 35 pathogenic, 40 likely-pathogenic
• Phenotypes (HPO): 44
• Cancer dependency (DepMap): dependent in 30.5% of screened cell lines
• MANE Select transcript: NM_005726

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12367
Approved symbol	TSFM
Name	Ts translation elongation factor, mitochondrial
Location	12q14.1
Locus type	gene with protein product
Status	Approved
Aliases	EF-Tsmt, EF-TS
Ensembl gene	ENSG00000123297
Ensembl biotype	protein_coding
OMIM	604723
Entrez	10102

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 16 protein_coding, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000323833, ENST00000417094, ENST00000434359, ENST00000457189, ENST00000497617, ENST00000540550, ENST00000543727, ENST00000548851, ENST00000550559, ENST00000651066, ENST00000651899, ENST00000652027, ENST00000872064, ENST00000872066, ENST00000872069, ENST00000935487, ENST00000935488, ENST00000935489, ENST00000935490, ENST00000943173

RefSeq mRNA: 4 — MANE Select: NM_005726 NM_001172695, NM_001172696, NM_001172697, NM_005726

CCDS: CCDS53809, CCDS53810, CCDS53811, CCDS8958

Canonical transcript exons

ENST00000652027 — 6 exons

Exon	Start	End
ENSE00001599913	57796177	57797587
ENSE00003508333	57787040	57787162
ENSE00003593624	57783110	57783283
ENSE00003638316	57786163	57786291
ENSE00003788498	57792986	57793073
ENSE00003902949	57782787	57782858

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 95.73.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 33.0951 / max 473.7850, expressed in 1817 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
126334	33.0951	1817

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland	UBERON:0001233	95.73	gold quality
left adrenal gland	UBERON:0001234	95.07	gold quality
right adrenal gland cortex	UBERON:0035827	95.03	gold quality
adrenal gland	UBERON:0002369	94.52	gold quality
left adrenal gland cortex	UBERON:0035825	94.29	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	93.33	gold quality
skeletal muscle tissue	UBERON:0001134	92.92	gold quality
gastrocnemius	UBERON:0001388	92.80	gold quality
islet of Langerhans	UBERON:0000006	92.69	gold quality
muscle of leg	UBERON:0001383	92.64	gold quality
heart left ventricle	UBERON:0002084	92.46	gold quality
mucosa of transverse colon	UBERON:0004991	92.21	gold quality
apex of heart	UBERON:0002098	92.08	gold quality
adrenal tissue	UBERON:0018303	91.99	gold quality
rectum	UBERON:0001052	91.54	gold quality
adult mammalian kidney	UBERON:0000082	91.51	gold quality
hindlimb stylopod muscle	UBERON:0004252	91.28	gold quality
muscle tissue	UBERON:0002385	91.12	gold quality
right lobe of liver	UBERON:0001114	90.98	gold quality
prefrontal cortex	UBERON:0000451	90.90	gold quality
heart	UBERON:0000948	90.90	gold quality
duodenum	UBERON:0002114	90.59	gold quality
liver	UBERON:0002107	90.48	gold quality
kidney	UBERON:0002113	90.13	gold quality
vermiform appendix	UBERON:0001154	89.78	gold quality
right atrium auricular region	UBERON:0006631	89.66	gold quality
frontal cortex	UBERON:0001870	89.63	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	89.08	gold quality
right testis	UBERON:0004534	88.97	gold quality
smooth muscle tissue	UBERON:0001135	88.94	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-84465	yes	909.05
E-ANND-3	yes	5.49

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTCF, MYC, SPI1

miRNA regulators (miRDB)

74 targeting TSFM, 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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
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
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 30.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 5)

• Molecular modeling showed that the Arg333Trp substitution disrupts local subdomain structure and the dimerization interface. (PMID:17033963)
• identified a homozygous mutation changing a highly conserved arginine into a tryptophan (R312W) in a kindred with intrauterine growth retardation, neonatal lactic acidosis, liver dysfunction and multiple respiratory chain deficiency in muscle (PMID:21741925)
• show that in addition to early-onset cardiomyopathy, TSFM mutations should be considered in childhood and juvenile encephalopathies with optic and/or peripheral neuropathy, ataxia, or Leigh disease (PMID:25037205)
• Different TSFM mutations can produce the same or very different clinical phenotypes, going from abortions to moderately severe presentations. On the other hand, the same TSFM mutation can also produce same or different phenotypes within the same range of presentations, therefore suggesting the involvement of unknown factors. (PMID:27677415)
• Short-term regulation of TSFM level does not alter amyloidogenesis and mitochondrial function in type-specific cells. (PMID:38578353)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tsfm	ENSDARG00000060748
mus_musculus	Tsfm	ENSMUSG00000040521
rattus_norvegicus	Tsfm	ENSRNOG00000048843
drosophila_melanogaster	mEFTs	FBGN0032646
caenorhabditis_elegans		WBGENE00010094

Protein

Protein identifiers

Elongation factor Ts, mitochondrial — P43897 (reviewed: P43897)

All UniProt accessions (9): A0A494C1D5, A0A494C1M9, C9JG32, C9JT21, E5KS95, P43897, F8VPA7, F8VS27, F8WCK2

UniProt curated annotations — full annotation on UniProt →

Function. Associates with the EF-Tu.GDP complex and induces the exchange of GDP to GTP. It remains bound to the aminoacyl-tRNA.EF-Tu.GTP complex up to the GTP hydrolysis stage on the ribosome. Participates in mitochondrial translation.

Subcellular location. Mitochondrion matrix.

Tissue specificity. Expressed in all tissues, with the highest levels of expression in skeletal muscle, liver and kidney.

Disease relevance. Combined oxidative phosphorylation deficiency 3 (COXPD3) [MIM:610505] A mitochondrial disease resulting in severe metabolic acidosis with encephalomyopathy or with hypertrophic cardiomyopathy. Patients show a severe defect in mitochondrial translation leading to a failure to assemble adequate amounts of three of the oxidative phosphorylation complexes. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Protein biosynthesis; polypeptide chain elongation.

Similarity. Belongs to the EF-Ts family.

Isoforms (4)

UniProt ID	Names	Canonical?
P43897-1	1	yes
P43897-2	2
P43897-3	3
P43897-4	4

RefSeq proteins (4): NP_001166166, NP_001166167, NP_001166168, NP_005717* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001816	Transl_elong_EFTs/EF1B	Family
IPR009060	UBA-like_sf	Homologous_superfamily
IPR014039	Transl_elong_EFTs/EF1B_dimer	Domain
IPR018101	Transl_elong_Ts_CS	Conserved_site
IPR036402	EF-Ts_dimer_sf	Homologous_superfamily

Pfam: PF00889, PF25025

UniProt features (23 total): splice variant 5, sequence variant 5, modified residue 5, helix 3, sequence conflict 2, transit peptide 1, chain 1, strand 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2CP9	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P43897-F1	87.87	0.79

Functional residue map

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

Post-translational modifications (5): 76, 133, 192, 270, 324

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5389840	Mitochondrial translation elongation

MSigDB gene sets: 240 (showing top): BROWNE_HCMV_INFECTION_8HR_UP, SHEPARD_CRASH_AND_BURN_MUTANT_UP, GOBP_MITOCHONDRIAL_TRANSLATION, GOBP_TRANSLATION, BROWNE_HCMV_INFECTION_24HR_UP, NIKOLSKY_BREAST_CANCER_12Q13_Q21_AMPLICON, GARY_CD5_TARGETS_DN, GOBP_TRANSLATIONAL_ELONGATION, DODD_NASOPHARYNGEAL_CARCINOMA_UP, WONG_MITOCHONDRIA_GENE_MODULE, MARTINEZ_RESPONSE_TO_TRABECTEDIN_DN, PARENT_MTOR_SIGNALING_UP, BROWNE_HCMV_INFECTION_14HR_UP, GOMF_GUANYL_NUCLEOTIDE_EXCHANGE_FACTOR_ACTIVITY, GOMF_TRANSLATION_ELONGATION_FACTOR_ACTIVITY

GO Biological Process (3): mitochondrial translational elongation (GO:0070125), translation (GO:0006412), translational elongation (GO:0006414)

GO Molecular Function (4): RNA binding (GO:0003723), translation elongation factor activity (GO:0003746), guanyl-nucleotide exchange factor activity (GO:0005085), protein binding (GO:0005515)

GO Cellular Component (3): nucleoplasm (GO:0005654), mitochondrion (GO:0005739), intracellular organelle lumen (GO:0070013)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Mitochondrial translation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
translational elongation	3
macromolecule biosynthetic process	2
mitochondrion	1
mitochondrial translation	1
peptidyltransferase activity	1
translational initiation	1
translational termination	1
protein metabolic process	1
protein biosynthetic process	1
translation	1
nucleic acid binding	1
translation factor activity	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
binding	1
nuclear lumen	1
cellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1
intracellular organelle	1
organelle lumen	1

Protein interactions and networks

STRING

2749 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TSFM	GFM1	Q96RP9	980
TSFM	TUFM	P49411	978
TSFM	MRPS16	Q9Y3D3	923
TSFM	MRPS22	P82650	895
TSFM	MRRF	Q96E11	866
TSFM	EIF5B	O60841	851
TSFM	GFM2	Q969S9	831
TSFM	ATP5IF1	Q9UII2	830
TSFM	TACO1	Q9BSH4	800
TSFM	HOGA1	Q86XE5	770
TSFM	LARS2	Q15031	739
TSFM	LARS1	Q9P2J5	739
TSFM	AARS2	Q5JTZ9	716
TSFM	AARS1	P49588	696
TSFM	EEF1B2	P24534	695

IntAct

99 interactions, top by confidence:

A	B	Type	Score
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
TSFM	CEP70	psi-mi:“MI:0915”(physical association)	0.670
TSFM	RALBP1	psi-mi:“MI:0915”(physical association)	0.670
GAS8	TSFM	psi-mi:“MI:0915”(physical association)	0.560
TSFM	MDFI	psi-mi:“MI:0915”(physical association)	0.560
TSFM	CPLX2	psi-mi:“MI:0915”(physical association)	0.560
TSFM	CCDC89	psi-mi:“MI:0915”(physical association)	0.560
GOLGA6L9	TSFM	psi-mi:“MI:0915”(physical association)	0.560
TSFM	KRTAP1-1	psi-mi:“MI:0915”(physical association)	0.560
TSFM	CST4	psi-mi:“MI:0914”(association)	0.530
TSFM	MTIF2	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
TSFM	SERBP1	psi-mi:“MI:0915”(physical association)	0.400
YWHAZ	TSFM	psi-mi:“MI:0915”(physical association)	0.400
TSFM	PPP1R12C	psi-mi:“MI:0915”(physical association)	0.370
TSFM	LIG4	psi-mi:“MI:0915”(physical association)	0.370
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
DLD	NFKBIE	psi-mi:“MI:0914”(association)	0.350
DLST		psi-mi:“MI:0914”(association)	0.350
MKI67	ARHGAP10	psi-mi:“MI:0914”(association)	0.350
GTF2E2	UBA6	psi-mi:“MI:0914”(association)	0.350
OXLD1	NUDT19	psi-mi:“MI:0914”(association)	0.350
MRPL12		psi-mi:“MI:0914”(association)	0.350
ATP5F1D		psi-mi:“MI:0914”(association)	0.350

BioGRID (438): TSFM (Affinity Capture-MS), TSFM (Affinity Capture-MS), TSFM (Affinity Capture-MS), TSFM (Affinity Capture-MS), TSFM (Proximity Label-MS), TSFM (Proximity Label-MS), TSFM (Proximity Label-MS), TSFM (Affinity Capture-MS), TSFM (Affinity Capture-MS), CEP70 (Two-hybrid), PPP1R12C (Two-hybrid), RALBP1 (Two-hybrid), ATXN7L2 (Affinity Capture-MS), AMY1C (Affinity Capture-MS), MTIF2 (Affinity Capture-MS)

ESM2 similar proteins: A0AVT1, A1A5Z3, A1L2P7, A4HH79, A4I4C5, A5CE05, A7SPW6, A8QE76, A8Y3X9, A9UMP7, B0BAD4, B0BM20, B0CRK4, B0WC25, B4FHF0, B5X5B4, B6K2P1, B8BAI9, B8PE34, B8PHE1, B9SEZ6, C3YEM5, D3BAV8, O45228, O84686, P43897, P71146, Q17PI0, Q1MRE2, Q20819, Q252Q6, Q29LW1, Q3KL15, Q4D248, Q4DW94, Q4FXY8, Q5L764, Q5XF75, Q66I84, Q6GMB0

Diamond homologs: A1A5Z3, A1B8E8, A1L2P7, A4YVG5, A5FZ68, A5ICK9, A5VQT2, A6U8K3, A6X0J2, A7HY18, A7INR5, A7SPW6, A8F0J0, A8GM33, A8GQP8, A8GUK0, A8I464, A8QE76, A8Y3X9, A9ISK1, A9M5H3, A9W4G4, B0BW39, B0CGV8, B0SZ20, B0UCS1, B0WC25, B1LTQ7, B1ZLB6, B2IGT1, B2S610, B3CNH0, B3PYP3, B3Q7K3, B4RBZ3, B5X5B4, B5ZN84, B6ISV0, B7KZG1, B8EKA0

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 104 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.

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial large ribosomal subunit assembly	5	52.7×	2e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	35
Likely pathogenic	40
Uncertain significance	175
Likely benign	262
Benign	16

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1071017	NC_000012.11:g.(?58176575)(58186866_?)del	Pathogenic
1071018	NC_000012.11:g.(?58186759)(58190376_?)del	Pathogenic
1075021	NM_005726.6(TSFM):c.536_549del (p.Glu179fs)	Pathogenic
1323719	NM_005726.6(TSFM):c.748G>T (p.Glu250Ter)	Pathogenic
1354493	NC_000012.12:g.57783110del	Pathogenic
1418980	NM_005726.6(TSFM):c.647dup (p.Tyr216Ter)	Pathogenic
1419710	NM_005726.6(TSFM):c.395T>A (p.Leu132Ter)	Pathogenic
1451378	NM_005726.6(TSFM):c.518del (p.Pro173fs)	Pathogenic
1452867	NC_000012.11:g.(?58176575)(58176651_?)del	Pathogenic
1453442	NM_005726.6(TSFM):c.597_598insTTTTTTTTTTTTTTTTTTNNNNNNNNNNGGGAGAGGGAGAGGGAGACGGGAGAGGGAGAGGGAGACGGGAGAGGGAGAGGGAGACGGGAGAGGGAGAGGGAGACGGGAGAGGGAGTGGGAGACGGGGAAAACATGATTCTT (p.Leu199_Lys200insPhePhePhePhePhePheXaaXaaXaaXaaGluArgGluArgGluThrGlyGluGlyGluGlyAspGlyArgGlyArgGlyArgArgGluArgGluArgGluThrGlyGluGlyValGlyAspGlyGluAsnMetIleLeu)	Pathogenic
1455737	NM_005726.6(TSFM):c.800_801del (p.Ser267fs)	Pathogenic
1459676	NC_000012.11:g.(?58186759)(58186866_?)del	Pathogenic
2059617	NM_005726.6(TSFM):c.647del (p.Tyr216fs)	Pathogenic
2097083	NM_005726.6(TSFM):c.929_930del (p.Phe310fs)	Pathogenic
2124572	NM_005726.6(TSFM):c.664C>T (p.Gln222Ter)	Pathogenic
2423923	NC_000012.11:g.(?58185728)(58186876_?)del	Pathogenic
2698339	NM_005726.6(TSFM):c.192dup (p.Lys65fs)	Pathogenic
2699349	NM_005726.6(TSFM):c.350dup (p.Leu118fs)	Pathogenic
2732013	NM_005726.6(TSFM):c.472_473dup (p.Tyr159fs)	Pathogenic
2755976	NM_005726.6(TSFM):c.374_375del (p.Thr125fs)	Pathogenic
2768235	NM_005726.6(TSFM):c.598A>T (p.Lys200Ter)	Pathogenic
2806699	NM_005726.6(TSFM):c.119dup (p.Ser41fs)	Pathogenic
2833928	NM_005726.6(TSFM):c.922del (p.Val307_Val308insTer)	Pathogenic
2989620	NM_005726.6(TSFM):c.716del (p.Ile239fs)	Pathogenic
3244362	NC_000012.11:g.(?58189940)(58190366_?)del	Pathogenic
3244363	NC_000012.11:g.(?58176585)(58180965_?)del	Pathogenic
3616110	NM_005726.6(TSFM):c.395T>G (p.Leu132Ter)	Pathogenic
3644879	NM_005726.6(TSFM):c.535_536del (p.Glu179fs)	Pathogenic
3667827	NM_005726.6(TSFM):c.664_667dup (p.Ser223fs)	Pathogenic
3725184	NM_005726.6(TSFM):c.866dup (p.Leu289fs)	Pathogenic

SpliceAI

2522 predictions. Top by Δscore:

Variant	Effect	Δscore
12:57783281:CAG:C	donor_loss	1.0000
12:57783282:AG:A	donor_loss	1.0000
12:57786154:A:AG	acceptor_gain	1.0000
12:57786155:A:G	acceptor_gain	1.0000
12:57786156:T:G	acceptor_gain	1.0000
12:57786158:TACA:T	acceptor_loss	1.0000
12:57786159:A:AG	acceptor_gain	1.0000
12:57786159:ACAG:A	acceptor_gain	1.0000
12:57786160:C:G	acceptor_gain	1.0000
12:57786160:CA:C	acceptor_loss	1.0000
12:57786161:A:AG	acceptor_gain	1.0000
12:57786161:AG:A	acceptor_gain	1.0000
12:57786162:G:GT	acceptor_gain	1.0000
12:57786162:GG:G	acceptor_gain	1.0000
12:57786162:GGC:G	acceptor_gain	1.0000
12:57786162:GGCA:G	acceptor_gain	1.0000
12:57786265:G:GT	donor_gain	1.0000
12:57786289:GAG:G	donor_gain	1.0000
12:57787036:ACAGG:A	acceptor_loss	1.0000
12:57787037:CA:C	acceptor_loss	1.0000
12:57787038:A:AC	acceptor_loss	1.0000
12:57787039:G:GT	acceptor_loss	1.0000
12:57787158:GTAAA:G	donor_gain	1.0000
12:57787159:TAAA:T	donor_gain	1.0000
12:57787159:TAAAG:T	donor_loss	1.0000
12:57787160:AAAGT:A	donor_loss	1.0000
12:57787161:AAGT:A	donor_loss	1.0000
12:57787162:AG:A	donor_loss	1.0000
12:57787163:G:GG	donor_gain	1.0000
12:57787164:T:A	donor_loss	1.0000

AlphaMissense

2076 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:57787058:T:C	F127L	0.997
12:57787060:T:A	F127L	0.997
12:57787060:T:G	F127L	0.997
12:57787048:T:G	C123W	0.996
12:57787047:G:A	C123Y	0.995
12:57787062:T:A	V128D	0.994
12:57796533:T:C	F310L	0.994
12:57796535:T:A	F310L	0.994
12:57796535:T:G	F310L	0.994
12:57783244:C:G	C64W	0.993
12:57787053:C:T	T125I	0.993
12:57796318:T:A	V238D	0.993
12:57787046:T:C	C123R	0.992
12:57787079:T:C	F134L	0.992
12:57787081:T:A	F134L	0.992
12:57787081:T:G	F134L	0.992
12:57796311:G:C	A236P	0.992
12:57796384:T:A	V260E	0.992
12:57786176:T:C	L82P	0.991
12:57786248:T:C	L106P	0.991
12:57787080:T:C	F134S	0.991
12:57787092:T:A	V138D	0.991
12:57796257:C:G	H218D	0.991
12:57787059:T:G	F127C	0.989
12:57796189:A:T	E195V	0.989
12:57796207:G:C	R201P	0.989
12:57796209:G:C	A202P	0.989
12:57796399:C:A	P265H	0.989
12:57783243:G:A	C64Y	0.988
12:57786244:G:C	G105R	0.988

dbSNP variants (sampled 300 via entrez): RS1000194361 (12:57793633 A>G), RS1000266944 (12:57788622 G>A), RS1000293278 (12:57793380 G>A,C), RS1000319671 (12:57789007 A>G), RS1000565826 (12:57782764 A>C,G), RS1000613742 (12:57802147 T>C), RS1000622382 (12:57790417 G>GC), RS1000627681 (12:57794915 A>G), RS1000675189 (12:57794491 G>A), RS1000680389 (12:57800361 C>G), RS1000898397 (12:57801664 C>A), RS1001025782 (12:57783058 C>A,T), RS1001176366 (12:57784128 A>C,G), RS1001305692 (12:57788374 G>C,T), RS1001688445 (12:57799032 A>G)

Disease associations

OMIM: gene MIM:604723 | disease phenotypes: MIM:610505, MIM:618594

GenCC curated gene-disease

Disease	Classification	Inheritance
fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR
Leigh syndrome	Moderate	AR

Mondo (4): fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3 (MONDO:0012512), dilated cardiomyopathy (MONDO:0005021), skeletal muscle disorder (MONDO:0020120), nephrotic syndrome, type 21 (MONDO:0032826)

Orphanet (3): Fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3 (Orphanet:168566), Dilated cardiomyopathy (Orphanet:217604), Skeletal muscle disease (Orphanet:98472)

HPO phenotypes

44 total (30 of 44 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000505	Visual impairment
HP:0000648	Optic atrophy
HP:0000741	Apathy
HP:0001138	Optic neuropathy
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0001298	Encephalopathy
HP:0001319	Neonatal hypotonia
HP:0001324	Muscle weakness
HP:0001332	Dystonia
HP:0001337	Tremor
HP:0001511	Intrauterine growth retardation
HP:0001522	Death in infancy
HP:0001558	Decreased fetal movement
HP:0001643	Patent ductus arteriosus
HP:0001644	Dilated cardiomyopathy
HP:0001655	Patent foramen ovale
HP:0001987	Hyperammonemia
HP:0002033	Poor suck
HP:0002069	Bilateral tonic-clonic seizure
HP:0002093	Respiratory insufficiency
HP:0002094	Dyspnea
HP:0002119	Ventriculomegaly
HP:0002151	Increased circulating lactate concentration
HP:0002240	Hepatomegaly
HP:0002878	Respiratory failure

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST004250_41	Alanine aminotransferase (ALT) levels after remission induction therapy in actute lymphoblastic leukemia (ALL)	4.000000e-06
GCST004250_49	Alanine aminotransferase (ALT) levels after remission induction therapy in actute lymphoblastic leukemia (ALL)	4.000000e-06
GCST005531_57	Multiple sclerosis	9.000000e-22
GCST010703_209	Brain morphology (MOSTest)	2.000000e-11

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007965	response to combination chemotherapy
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
C566467	Combined Oxidative Phosphorylation Deficiency 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	3
Acetaminophen	decreases expression	3
Quercetin	increases expression, decreases expression	3
Valproic Acid	affects methylation, increases expression	3
Cadmium Chloride	decreases expression, increases abundance, increases expression	3
mercuric bromide	decreases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
beta-lapachone	increases expression	1
perfluorooctanoic acid	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases reaction, increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
NSC 689534	affects binding, decreases expression	1
bisphenol AF	increases expression	1
Arsenic	decreases expression, increases abundance	1
Atrazine	decreases expression	1
Vehicle Emissions	decreases reaction, increases expression	1
Cadmium	increases abundance, increases expression	1
Cannabidiol	increases expression	1
Copper	affects binding, decreases expression	1
Estradiol	affects binding, increases reaction	1
Ethyl Methanesulfonate	decreases expression	1
Formaldehyde	decreases expression	1
Ivermectin	decreases expression	1
Ribonucleotides	affects binding	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_XU78	HAP1 TSFM (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00374465	PHASE4	UNKNOWN	Therapy With Verapamil or Carvedilol in Chronic Heart Failure
NCT01293903	PHASE4	COMPLETED	Study of Qiliqiangxin Capsule to Treat Dilated Cardiomyopathy
NCT01557140	PHASE4	COMPLETED	A Randomized Trial of Carvedilol in Chronic Chagas Cardiomyopathy
NCT01917149	PHASE4	COMPLETED	Supramaximal Titrated Inhibition of RAAS in Dilated Cardiomyopathy
NCT02115581	PHASE4	COMPLETED	Coenzyme Q10 Supplementation in Children With Idiopathic Dilated Cardiomyopathy
NCT06236022	PHASE4	RECRUITING	The Effects of Sirolimus in Patients With Dilated Cardiomyopathy Infected With Kaposi Sarcoma-associated Virus
NCT00333827	PHASE3	COMPLETED	Cell Therapy In Dilated Cardiomyopathy
NCT00505154	PHASE3	COMPLETED	Effect of Rosuvastatin on Left Ventricular Remodeling
NCT01223703	PHASE3	COMPLETED	PUFAs and Left Ventricular Function in Heart Failure
NCT01583114	PHASE3	TERMINATED	PREclinical Mutation CARriers From Families With DIlated Cardiomyopathy and ACE Inhibitors
NCT01914081	PHASE3	UNKNOWN	Resveratrol: A Potential Anti- Remodeling Agent in Heart Failure, From Bench to Bedside
NCT02989181	PHASE3	UNKNOWN	Continues Positive Airway Pressure Treatment for Patients With Dilated Cardiomyopathy and Obstructive Sleep Apnea
NCT03439514	PHASE3	TERMINATED	A Study of ARRY-371797 (PF-07265803) in Patients With Symptomatic Dilated Cardiomyopathy Due to a Lamin A/C Gene Mutation
NCT05237323	PHASE3	COMPLETED	Micophenolate Mofetil Versus Azathioprine in Myocarditis
NCT05849766	PHASE3	COMPLETED	Effect of Dapagliflozin on Cardiac Structure, Function and Secondary Mitral Regurgitation in Patients with Left Ventricle Dysfunction
NCT06250257	PHASE3	RECRUITING	Bromocriptine in Dilated Cardiomyopathy Among Women of Reproductive Age
NCT00629018	PHASE2	COMPLETED	Safety and Efficacy Study of Stem Cell Transplantation to Treat Dilated Cardiomyopathy
NCT00629096	PHASE2	COMPLETED	Intracoronary Infusion of Autologous Bone Marrow Cells for Treatment of Idiopathic Dilated Cardiomyopathy
NCT00765518	PHASE2	COMPLETED	Use of Ixmyelocel-T (Formerly Cardiac Repair Cell [CRC] Treatment) in Patients With Heart Failure Due to Dilated Cardiomyopathy (IMPACT-DCM)
NCT00847964	PHASE2	COMPLETED	Safety and Feasibility of Algisyl-LVR™ as a Method of Left Ventricular Restoration in Patients With DCM Undergoing Open-heart Surgery
NCT01020968	PHASE2	COMPLETED	Use of Ixmyelocel-T (Formerly Catheter-based Cardiac Repair Cell [CRC]) Treatment in Patients With Heart Failure Due to Dilated Cardiomyopathy
NCT01302171	PHASE2	COMPLETED	Bone Marrow Derived Adult Stem Cells for Dilated Cardiomyopathy
NCT01350310	PHASE2	COMPLETED	Safety and Efficacy Study of Intramyocardial Stem Cell Therapy in Patients With Dilated Cardiomyopathy
NCT02133911	PHASE2	COMPLETED	A Pilot Trial of Ranolazine to Treat Patients With Dilated Cardiomyopathy
NCT03071653	PHASE2	SUSPENDED	Left Cardiac Sympathetic Denervation for Cardiomyopathy Feasibility Pilot Study
NCT03572660	PHASE2	ACTIVE_NOT_RECRUITING	Use of Bone Marrow Derived Stem Cell and G-CSF With Circulatory Assistance in the Treatment of DCM
NCT03775070	PHASE2	COMPLETED	Simvastatin Therapy in Patients With Dilated Cardiomyopathy.
NCT04405804	PHASE2	UNKNOWN	Early Administration of Ivabradine in Children With Heart Failure
NCT05410873	PHASE2	COMPLETED	Examining the Effects of Mitochondrial Oxidative Stress in DCM
NCT06632834	PHASE2	RECRUITING	Outcome-targeted Therapy: Principle and Outcome Evaluation: Clinical Study and Phenotype-genotype Correlation
NCT00585546	PHASE1	TERMINATED	Harefield Recovery Protocol Study for Patients With Refractory Chronic Heart Failure
NCT02293603	PHASE1	UNKNOWN	Dilated cardiomYopathy iNtervention With Allogeneic MyocardIally-regenerative Cells (DYNAMIC)
NCT03062956	PHASE1	COMPLETED	A Single Ascending Dose Study Assessing the Safety, Tolerability, PK and PD of MYK-491
NCT03129568	PHASE1	COMPLETED	Transcoronary Infusion of Cardiac Progenitor Cells in Pediatric Dilated Cardiomyopathy
NCT04982081	PHASE1	UNKNOWN	Treating Congestive HF With hiPSC-CMs Through Endocardial Injection
NCT06381466	PHASE1	TERMINATED	A Study to Investigate Safety, Tolerability, and Pharmacokinetics of Oral AZD0233 Compared With Placebo in Healthy Adult Participants.
NCT06464588	PHASE1	RECRUITING	A Phase 1 Open-Label Study of the Safety of Intravenous Allogeneic Neonatal Mesenchymal Cells (nMSCs) in Young Adult (1A) and Pediatric (1B) Patients With Dilated Cardiomyopathy (DCM)
NCT06902896	PHASE1	COMPLETED	Safety and Efficacy of FAP iCDC in End-stage Dilated Cardiomyopathy
NCT07137338	PHASE1	RECRUITING	A Phase 1 AAV Gene Therapy Trial Evaluating Safety and Preliminary Efficacy of RP-A701 in Subjects With BAG3 Dilated Cardiomyopathy
NCT07241104	PHASE1	RECRUITING	A Study of AZD4063 in PLN R14del Dilated Cardiomyopathy