GFM1

Summary

GFM1 (G elongation factor mitochondrial 1, HGNC:13780) is a protein-coding gene on chromosome 3q25.32, encoding Elongation factor G, mitochondrial (Q96RP9). Mitochondrial GTPase that catalyzes the GTP-dependent ribosomal translocation step during translation elongation. It is a selective cancer dependency (DepMap: 54.5% of cell lines).

Eukaryotes contain two protein translational systems, one in the cytoplasm and one in the mitochondria. Mitochondrial translation is crucial for maintaining mitochondrial function and mutations in this system lead to a breakdown in the respiratory chain-oxidative phosphorylation system and to impaired maintenance of mitochondrial DNA. This gene encodes one of the mitochondrial translation elongation factors. Its role in the regulation of normal mitochondrial function and in different disease states attributed to mitochondrial dysfunction is not known.

Source: NCBI Gene 85476 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hepatoencephalopathy due to combined oxidative phosphorylation defect type 1 (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 1,057 total — 63 pathogenic, 100 likely-pathogenic
• Phenotypes (HPO): 44
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 54.5% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_024996

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13780
Approved symbol	GFM1
Name	G elongation factor mitochondrial 1
Location	3q25.32
Locus type	gene with protein product
Status	Approved
Aliases	EFGM, GFM, EGF1, mtEF-G1
Ensembl gene	ENSG00000168827
Ensembl biotype	protein_coding
OMIM	606639
Entrez	85476

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 17 protein_coding, 4 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000264263, ENST00000312756, ENST00000464732, ENST00000472383, ENST00000477721, ENST00000478251, ENST00000478254, ENST00000478576, ENST00000481468, ENST00000486715, ENST00000490261, ENST00000867684, ENST00000867685, ENST00000867686, ENST00000867687, ENST00000867688, ENST00000867689, ENST00000867690, ENST00000916372, ENST00000960374, ENST00000960375, ENST00000960376, ENST00000960377

RefSeq mRNA: 10 — MANE Select: NM_024996 NM_001308164, NM_001308166, NM_001374355, NM_001374356, NM_001374357, NM_001374358, NM_001374359, NM_001374360, NM_001374361, NM_024996

CCDS: CCDS33885, CCDS77851, CCDS82867

Canonical transcript exons

ENST00000486715 — 18 exons

Exon	Start	End
ENSE00001506201	158658922	158659059
ENSE00001930303	158691336	158695581
ENSE00001933961	158644527	158644715
ENSE00002206405	158652096	158652246
ENSE00002253828	158646743	158646947
ENSE00002268305	158646165	158646297
ENSE00002299466	158649041	158649157
ENSE00003488749	158690163	158690323
ENSE00003512738	158662628	158662684
ENSE00003556308	158645629	158645781
ENSE00003557727	158654547	158654631
ENSE00003574631	158681995	158682157
ENSE00003593938	158665337	158665474
ENSE00003614106	158691139	158691192
ENSE00003617330	158666304	158666386
ENSE00003643522	158653310	158653467
ENSE00003668323	158660874	158660975
ENSE00003689176	158684524	158684668

Expression profiles

Bgee: expression breadth ubiquitous, 271 present calls, max score 98.81.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 42.5934 / max 238.8882, expressed in 1821 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
39505	42.2309	1821
39506	0.3625	171

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	98.81	gold quality
biceps brachii	UBERON:0001507	96.61	gold quality
adrenal tissue	UBERON:0018303	96.46	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.16	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	96.14	gold quality
pigmented layer of retina	UBERON:0001782	95.77	gold quality
retina	UBERON:0000966	95.75	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	95.70	gold quality
heart right ventricle	UBERON:0002080	95.12	gold quality
germinal epithelium of ovary	UBERON:0001304	95.08	gold quality
mucosa of sigmoid colon	UBERON:0004993	95.02	gold quality
parietal pleura	UBERON:0002400	94.73	gold quality
substantia nigra pars compacta	UBERON:0001965	94.57	gold quality
colonic mucosa	UBERON:0000317	94.46	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	94.39	gold quality
substantia nigra pars reticulata	UBERON:0001966	94.35	gold quality
secondary oocyte	CL:0000655	94.19	gold quality
visceral pleura	UBERON:0002401	94.10	gold quality
jejunal mucosa	UBERON:0000399	94.05	gold quality
pons	UBERON:0000988	94.05	gold quality
rectum	UBERON:0001052	94.02	gold quality
middle temporal gyrus	UBERON:0002771	93.96	gold quality
gastrocnemius	UBERON:0001388	93.86	gold quality
body of tongue	UBERON:0011876	93.82	gold quality
lateral nuclear group of thalamus	UBERON:0002736	93.81	gold quality
renal medulla	UBERON:0000362	93.62	gold quality
muscle of leg	UBERON:0001383	93.62	gold quality
jejunum	UBERON:0002115	93.57	gold quality
gingival epithelium	UBERON:0001949	93.53	gold quality
skin of hip	UBERON:0001554	93.48	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.66

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EPAS1, ESRRA, FOXL2, FOXO3, GABPA, HIF1A, HNF4A, LITAF, MEIS1, MTF1, MYC, NFE2L2, NFKB, NR3C1, NR4A2, NRF1, PAX1, PAX3, PBX1, PBX2, PPARA, PPARG, RELA, SP1, SREBF1, STAT5A, TFAM, TFAP2A, THRA, TP53, TP63, YY1

miRNA regulators (miRDB)

54 targeting GFM1, 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-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-4517	99.76	69.19	1867
HSA-MIR-1179	99.71	68.70	1040
HSA-MIR-548AU-3P	99.70	68.22	1373
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-497-3P	99.61	69.71	1990
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-216A-5P	99.50	68.02	1288
HSA-MIR-578	99.46	68.36	1787
HSA-MIR-147B-5P	99.45	70.62	2432
HSA-MIR-5695	99.41	67.48	1047
HSA-MIR-889-3P	99.40	69.76	2103

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 54.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 12)

• analysis of molecular model for EF-G1 isoform (PMID:15358359)
• Sequencing of EFG1 revealed a mutation affecting a conserved residue of the guanosine triphosphate (GTP)-binding domain. These results define a new class of gene defects underlying disorders of oxidative phosphorylation. (PMID:15537906)
• mutations in the mitochondrial translation factor EFG1 may have a role in oxidative phosphorylation deficiencies [case report] (PMID:16632485)
• Genetic investigation of patients with defective mitochondrial translation led to the discovery of novel mutations in the mitochondrial elongation factor G1 (EFG1) in one affected baby and in the mitochondrial elongation factor Tu (EFTu) in another one (PMID:17160893)
• The R671C mutation disrupts an inter-subunit interface and could locally destabilize the mutant protein. The second mutation (L398P) disrupted the H-bond network in a rich-beta-sheet domain, and may have a dramatic effect on local structure. (PMID:21986555)
• In the present study, a nanoparticle modified with EGFP-EGF1 (ENP) was constructed as a multitargeting drug delivery system. The protein binding experiment showed EGFP-EGF1 could bind well to A549 tumor cells and other stromal cells including neo-vascular cells, tumor-associated fibroblasts, and tumor-associated macrophages (PMID:26890991)
• Functional studies demonstrated decreased GFM1 protein levels, suggested disrupted assembly of mitochondrial complexes III and V and decreased activities of mitochondrial complexes I and IV, all indicating combined OXPHOS deficiency. (PMID:28216230)
• Clinical, neuroimaging and biochemical findings in patients and patient fibroblasts expressing ten novel GFM1 mutations. (PMID:31680380)
• Structural insights into mammalian mitochondrial translation elongation catalyzed by mtEFG1. (PMID:32602580)
• Structures of the human mitochondrial ribosome bound to EF-G1 reveal distinct features of mitochondrial translation elongation. (PMID:32737313)
• [Analysis of GFM1 gene mutations in a family with combined oxidative phosphorylation deficiency 1]. (PMID:33210482)
• Whole exome sequencing identifies a novel compound heterozygous GFM1 variant underlying developmental delay, dystonia, polymicrogyria, and severe intellectual disability in a Pakhtun family. (PMID:35703069)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	gfm1	ENSDARG00000063624
mus_musculus	Gfm1	ENSMUSG00000027774
rattus_norvegicus	Gfm1	ENSRNOG00000012873
drosophila_melanogaster	mEFG1	FBGN0263133
caenorhabditis_elegans		WBGENE00009246

Paralogs (18): MTIF2 (ENSG00000085760), GTPBP1 (ENSG00000100226), EEF1A2 (ENSG00000101210), GSPT1 (ENSG00000103342), EFTUD2 (ENSG00000108883), HBS1L (ENSG00000112339), EIF2S3 (ENSG00000130741), EEFSEC (ENSG00000132394), EFL1 (ENSG00000140598), GUF1 (ENSG00000151806), EEF1A1 (ENSG00000156508), EIF5B (ENSG00000158417), GFM2 (ENSG00000164347), EEF2 (ENSG00000167658), GTPBP2 (ENSG00000172432), TUFM (ENSG00000178952), EIF2S3B (ENSG00000180574), GSPT2 (ENSG00000189369)

Protein

Protein identifiers

Elongation factor G, mitochondrial — Q96RP9 (reviewed: Q96RP9)

Alternative names: Elongation factor G 1, mitochondrial, Elongation factor G1

All UniProt accessions (6): C9IZ01, C9JA25, Q96RP9, E5KND5, F8WAU4, H7C5M4

UniProt curated annotations — full annotation on UniProt →

Function. Mitochondrial GTPase that catalyzes the GTP-dependent ribosomal translocation step during translation elongation. During this step, the ribosome changes from the pre-translocational (PRE) to the post-translocational (POST) state as the newly formed A-site-bound peptidyl-tRNA and P-site-bound deacylated tRNA move to the P and E sites, respectively. Catalyzes the coordinated movement of the two tRNA molecules, the mRNA and conformational changes in the ribosome. Does not mediate the disassembly of ribosomes from messenger RNA at the termination of mitochondrial protein biosynthesis.

Subcellular location. Mitochondrion.

Disease relevance. Combined oxidative phosphorylation deficiency 1 (COXPD1) [MIM:609060] A mitochondrial disease resulting in early rapidly progressive hepatoencephalopathy. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Protein biosynthesis; polypeptide chain elongation.

Similarity. Belongs to the TRAFAC class translation factor GTPase superfamily. Classic translation factor GTPase family. EF-G/EF-2 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96RP9-1	1	yes
Q96RP9-2	2

RefSeq proteins (10): NP_001295093, NP_001295095, NP_001361284, NP_001361285, NP_001361286, NP_001361287, NP_001361288, NP_001361289, NP_001361290, NP_079272* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000640	EFG_V-like	Domain
IPR000795	T_Tr_GTP-bd_dom	Domain
IPR004161	EFTu-like_2	Domain
IPR004540	Transl_elong_EFG/EF2	Family
IPR005225	Small_GTP-bd	Domain
IPR005517	Transl_elong_EFG/EF2_IV	Domain
IPR009000	Transl_B-barrel_sf	Homologous_superfamily
IPR009022	EFG_III	Domain
IPR014721	Ribsml_uS5_D2-typ_fold_subgr	Homologous_superfamily
IPR020568	Ribosomal_Su5_D2-typ_SF	Homologous_superfamily
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR031157	G_TR_CS	Conserved_site
IPR035647	EFG_III/V	Homologous_superfamily
IPR035649	EFG_V	Domain
IPR041095	EFG_II	Domain
IPR047872	EFG_IV	Domain

Pfam: PF00009, PF00679, PF03144, PF03764, PF14492

Catalyzed reactions (Rhea), 1 shown:

• GTP + H2O = GDP + phosphate + H(+) (RHEA:19669)

UniProt features (16 total): sequence variant 5, binding site 3, sequence conflict 2, modified residue 2, transit peptide 1, chain 1, domain 1, splice variant 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
6VMI	ELECTRON MICROSCOPY	2.96
6VLZ	ELECTRON MICROSCOPY	2.97
6YDP	ELECTRON MICROSCOPY	3
7A5K	ELECTRON MICROSCOPY	3.7
6YDW	ELECTRON MICROSCOPY	4.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96RP9-F1	82.36	0.34

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 (3): 53–60; 120–124; 174–177

Post-translational modifications (2): 91, 175

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5389840	Mitochondrial translation elongation

MSigDB gene sets: 233 (showing top): RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_MITOCHONDRIAL_TRANSLATION, GOBP_TRANSLATION, WEI_MYCN_TARGETS_WITH_E_BOX, GARY_CD5_TARGETS_DN, GOBP_TRANSLATIONAL_ELONGATION, DODD_NASOPHARYNGEAL_CARCINOMA_UP, IVANOVA_HEMATOPOIESIS_INTERMEDIATE_PROGENITOR, GOCC_MITOCHONDRIAL_MATRIX, GOMF_GTPASE_ACTIVITY, NUYTTEN_NIPP1_TARGETS_DN, GOMF_TRANSLATION_ELONGATION_FACTOR_ACTIVITY, GOMF_HYDROLASE_ACTIVITY_ACTING_ON_ACID_ANHYDRIDES, MATSUDA_NATURAL_KILLER_DIFFERENTIATION, chr3q25

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

GO Molecular Function (7): RNA binding (GO:0003723), translation elongation factor activity (GO:0003746), GTPase activity (GO:0003924), GTP binding (GO:0005525), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (2): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759)

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
mitochondrion	2
macromolecule biosynthetic process	2
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
ribonucleoside triphosphate phosphatase activity	1
guanyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

5341 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GFM1	TSFM	P43897	980
GFM1	MRRF	Q96E11	967
GFM1	MRPS16	Q9Y3D3	859
GFM1	MRPS22	P82650	837
GFM1	CYP4V2	Q6ZWL3	824
GFM1	MIEF2	Q96C03	810
GFM1	F3	P13726	801
GFM1	ATP5IF1	Q9UII2	797
GFM1	EGF	P01133	795
GFM1	HOGA1	Q86XE5	718
GFM1	EEF2	P13639	657
GFM1	F7	P08709	653
GFM1	EIF5B	O60841	648
GFM1	RPS12	P25398	632
GFM1	ZNF470	Q6ECI4	607

IntAct

64 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
HSPD1	NUDT19	psi-mi:“MI:0914”(association)	0.710
NDUFS7	NDUFS8	psi-mi:“MI:0914”(association)	0.640
YBEY	NME4	psi-mi:“MI:0914”(association)	0.530
UQCRFS1	NDUFAB1	psi-mi:“MI:0914”(association)	0.530
ERBB2	HAX1	psi-mi:“MI:0914”(association)	0.530
TRIM63	GFM1	psi-mi:“MI:0915”(physical association)	0.510
GFM1	TRIM63	psi-mi:“MI:0915”(physical association)	0.510
NS	GFM1	psi-mi:“MI:0915”(physical association)	0.500
GFM1	TPM3	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
GFM1	TRIM55	psi-mi:“MI:0915”(physical association)	0.400
GFM1	SMURF2	psi-mi:“MI:0915”(physical association)	0.370
Dda1	AKR7A2	psi-mi:“MI:0914”(association)	0.350
MAGOHB	GFM1	psi-mi:“MI:0914”(association)	0.350
FASTKD3	VWA8	psi-mi:“MI:0914”(association)	0.350
NS	PEX14	psi-mi:“MI:0914”(association)	0.350
BOLA1	NME4	psi-mi:“MI:0914”(association)	0.350
NDUFS3	ACOT7	psi-mi:“MI:0914”(association)	0.350
BOLA1	PMPCB	psi-mi:“MI:0914”(association)	0.350
MAPK13	DDX3X	psi-mi:“MI:0914”(association)	0.350
SLX4	SMAP	psi-mi:“MI:0914”(association)	0.350
	NUDT19	psi-mi:“MI:0914”(association)	0.350
HTRA4	PSMD12	psi-mi:“MI:0914”(association)	0.350
G3BP1	AGPS	psi-mi:“MI:0914”(association)	0.350

BioGRID (384): GFM1 (Two-hybrid), GFM1 (Two-hybrid), GFM1 (Reconstituted Complex), GFM1 (Reconstituted Complex), GFM1 (Affinity Capture-MS), GFM1 (Co-fractionation), RPL23A (Co-fractionation), TUFM (Co-fractionation), GFM1 (Affinity Capture-MS), GFM1 (Affinity Capture-MS), GFM1 (Affinity Capture-MS), GFM1 (Affinity Capture-MS), GFM1 (Affinity Capture-MS), GFM1 (Affinity Capture-MS), GFM1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0L0P6P7, A4I2L4, A5PKR8, A8D8P8, A9U328, A9VB27, A9ZSZ2, D3TQJ5, F4IE66, F4ISQ7, O22899, O43143, O54747, O60126, O61660, O70157, O76922, O95985, O96651, P13099, P54358, P90829, P97283, Q07803, Q08BB1, Q0J0S6, Q13472, Q20875, Q22307, Q23223, Q4P1V1, Q5R9V1, Q5RAZ4, Q5RBD4, Q5XQC7, Q7K3M5, Q80VY9, Q8K0D5, Q8T2T7, Q96RP9

Diamond homologs: A1CHC3, A1CXG4, A1VYJ8, A2QI77, A3GHT9, A5DK38, A5PKR8, A6Q1M7, A6RLH0, A7A0X4, A7EVV9, A7GZJ4, A7H4P5, A7I3T6, A7RR04, A7TFN8, A8FKR7, A8P1W0, A8PXR7, A8WTI8, A8Z6I6, B0DSK4, B0WGM1, B0Y604, B2UUV6, B2WBM8, B3LT39, B3MK91, B3N6A5, B4HY41, B4JQM7, B4KKD5, B4LS49, B4MZW9, B4NZM7, B4Q5D5, B5VN01, B5Z8J0, B6H460, B6JN34

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 73 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	74.0×	3e-06
mitochondrial translation	5	13.0×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1057 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	63
Likely pathogenic	100
Uncertain significance	259
Likely benign	453
Benign	62

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1028357	NM_024996.7(GFM1):c.1324G>T (p.Glu442Ter)	Pathogenic
1069103	NM_024996.7(GFM1):c.1346del (p.Pro449fs)	Pathogenic
1070155	NC_000003.11:g.(?158362414)(158409266_?)del	Pathogenic
1070156	NC_000003.11:g.(?158380407)(158384185_?)del	Pathogenic
1070157	NC_000003.11:g.(?158399774)(158402467_?)del	Pathogenic
1070355	NM_024996.7(GFM1):c.1466_1467del (p.Lys489fs)	Pathogenic
1322995	NM_024996.7(GFM1):c.1510del (p.Tyr504fs)	Pathogenic
1360761	NM_024996.7(GFM1):c.1096_1099del (p.Gly366fs)	Pathogenic
1361109	NM_024996.7(GFM1):c.649del (p.Ile218fs)	Pathogenic
1362126	NM_024996.7(GFM1):c.1217del (p.Met406fs)	Pathogenic
1362573	NM_024996.7(GFM1):c.136dup (p.Ile46fs)	Pathogenic
1367313	NC_000003.12:g.158684526del	Pathogenic
1379201	NM_024996.7(GFM1):c.1874_1875del (p.Ser625fs)	Pathogenic
1397569	NM_024996.7(GFM1):c.1167_1168insTT (p.Arg390fs)	Pathogenic
1450272	NM_024996.7(GFM1):c.1878del (p.Phe626fs)	Pathogenic
1452294	NM_024996.7(GFM1):c.612del (p.Met205fs)	Pathogenic
1453261	NM_024996.7(GFM1):c.769del (p.Val257fs)	Pathogenic
1453861	NM_024996.7(GFM1):c.1834C>T (p.Gln612Ter)	Pathogenic
1456222	NM_024996.7(GFM1):c.2064del (p.Leu687_Tyr688insTer)	Pathogenic
1457900	NM_024996.7(GFM1):c.1015dup (p.Thr339fs)	Pathogenic
1950634	NM_024996.7(GFM1):c.1393A>T (p.Lys465Ter)	Pathogenic
1991679	NM_024996.7(GFM1):c.1126G>T (p.Gly376Ter)	Pathogenic
2021918	NM_024996.7(GFM1):c.604C>T (p.Gln202Ter)	Pathogenic
2025162	NM_024996.7(GFM1):c.1589del (p.Thr530fs)	Pathogenic
2027734	NM_024996.7(GFM1):c.1406del (p.Gly469fs)	Pathogenic
2046755	NM_024996.7(GFM1):c.1474_1480del (p.Val492fs)	Pathogenic
2076421	NM_024996.7(GFM1):c.796G>T (p.Glu266Ter)	Pathogenic
2093073	NM_024996.7(GFM1):c.1239T>A (p.Tyr413Ter)	Pathogenic
2106481	NM_024996.7(GFM1):c.1470_1471del (p.Glu490fs)	Pathogenic
2107539	NM_024996.7(GFM1):c.1623_1624insG (p.Gln542fs)	Pathogenic

SpliceAI

3405 predictions. Top by Δscore:

Variant	Effect	Δscore
3:158645627:A:AG	acceptor_gain	1.0000
3:158645627:AGGT:A	acceptor_loss	1.0000
3:158645628:G:GG	acceptor_gain	1.0000
3:158645628:G:GT	acceptor_loss	1.0000
3:158645628:GGTT:G	acceptor_gain	1.0000
3:158645778:TGAGG:T	donor_loss	1.0000
3:158645779:G:GT	donor_gain	1.0000
3:158645780:AGG:A	donor_loss	1.0000
3:158645781:GGTA:G	donor_loss	1.0000
3:158645782:G:C	donor_loss	1.0000
3:158645783:T:G	donor_loss	1.0000
3:158646298:G:GG	donor_gain	1.0000
3:158649158:G:GG	donor_gain	1.0000
3:158652090:TCTTA:T	acceptor_loss	1.0000
3:158652091:CTTA:C	acceptor_loss	1.0000
3:158652092:TTA:T	acceptor_loss	1.0000
3:158652093:TA:T	acceptor_loss	1.0000
3:158652094:A:AG	acceptor_gain	1.0000
3:158652094:AG:A	acceptor_loss	1.0000
3:158652095:G:GG	acceptor_gain	1.0000
3:158652095:GTC:G	acceptor_gain	1.0000
3:158652095:GTCA:G	acceptor_gain	1.0000
3:158652214:G:GT	donor_gain	1.0000
3:158652243:AAAG:A	donor_loss	1.0000
3:158652244:AAG:A	donor_loss	1.0000
3:158652245:AG:A	donor_loss	1.0000
3:158652246:GG:G	donor_loss	1.0000
3:158652247:GCA:G	donor_loss	1.0000
3:158652249:AAGT:A	donor_loss	1.0000
3:158653305:T:A	acceptor_gain	1.0000

AlphaMissense

4906 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:158646754:T:C	F127L	1.000
3:158646756:C:A	F127L	1.000
3:158646756:C:G	F127L	1.000
3:158645719:G:T	G58W	0.999
3:158645720:G:A	G58E	0.999
3:158645722:A:C	K59Q	0.999
3:158645723:A:T	K59I	0.999
3:158645741:G:C	R65P	0.999
3:158646215:G:C	E95D	0.999
3:158646215:G:T	E95D	0.999
3:158646288:G:C	D120H	0.999
3:158646297:G:T	G123W	0.999
3:158646745:C:G	H124D	0.999
3:158646747:T:A	H124Q	0.999
3:158646747:T:G	H124Q	0.999
3:158646755:T:C	F127S	0.999
3:158646899:A:T	K175I	0.999
3:158654620:T:C	F358L	0.999
3:158654622:T:A	F358L	0.999
3:158654622:T:G	F358L	0.999
3:158665440:G:A	G495E	0.999
3:158665445:G:A	G497R	0.999
3:158665445:G:C	G497R	0.999
3:158666362:G:C	R526P	0.999
3:158682033:G:A	G547D	0.999
3:158682042:G:A	G550E	0.999
3:158684600:G:A	G614E	0.999
3:158684608:C:G	H617D	0.999
3:158684610:C:A	H617Q	0.999
3:158684610:C:G	H617Q	0.999

dbSNP variants (sampled 300 via entrez): RS1000121562 (3:158694362 T>C), RS1000126808 (3:158647882 T>G), RS1000269276 (3:158675299 A>C), RS1000319395 (3:158668351 G>A), RS1000408681 (3:158684675 T>A), RS1000463556 (3:158678566 G>T), RS1000477652 (3:158647552 A>G), RS1000758125 (3:158672869 A>T), RS1000820990 (3:158657653 GT>G,GTT), RS1000883729 (3:158661035 G>A), RS1000937577 (3:158651559 G>A), RS1000956753 (3:158687446 A>G,T), RS1000989727 (3:158651198 AC>A), RS1000997325 (3:158674048 T>C), RS1001003613 (3:158680167 T>C)

Disease associations

OMIM: gene MIM:606639 | disease phenotypes: MIM:609060, MIM:256000

GenCC curated gene-disease

Disease	Classification	Inheritance
hepatoencephalopathy due to combined oxidative phosphorylation defect type 1	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Leigh syndrome	Moderate	AR

Mondo (3): hepatoencephalopathy due to combined oxidative phosphorylation defect type 1 (MONDO:0012191), Leigh syndrome (MONDO:0009723), combined oxidative phosphorylation deficiency (MONDO:0000732)

Orphanet (2): Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1 (Orphanet:137681), Leigh syndrome (Orphanet:506)

HPO phenotypes

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

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000047	Hypospadias
HP:0000252	Microcephaly
HP:0000639	Nystagmus
HP:0000817	Reduced eye contact
HP:0001250	Seizure
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001276	Hypertonia
HP:0001298	Encephalopathy
HP:0001332	Dystonia
HP:0001347	Hyperreflexia
HP:0001396	Cholestasis
HP:0001399	Hepatic failure
HP:0001511	Intrauterine growth retardation
HP:0001622	Premature birth
HP:0001942	Metabolic acidosis
HP:0001943	Hypoglycemia
HP:0002079	Hypoplasia of the corpus callosum
HP:0002119	Ventriculomegaly
HP:0002151	Increased circulating lactate concentration
HP:0002240	Hepatomegaly
HP:0002283	Global brain atrophy
HP:0002353	EEG abnormality
HP:0002375	Hypokinesia
HP:0002490	Increased CSF lactate
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0003073	Hypoalbuminemia
HP:0003128	Lactic acidosis

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST003623_1	diarrhoeal disease at age 2	3.000000e-06
GCST007611_15	Chronic obstructive pulmonary disease or high blood pressure (pleiotropy)	1.000000e-09

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D007888	Leigh Disease	C10.228.140.163.100.412; C16.320.565.189.412; C16.320.565.202.810.444; C18.452.132.100.412; C18.452.648.189.412; C18.452.648.202.810.444; C18.452.660.520
C563797	Combined Oxidative Phosphorylation Deficiency 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067436 (SINGLE PROTEIN)

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

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	92.81	nM	CHEMBL3752910
6.87	ED50	136.2	nM	CHEMBL3752910

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-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149863: Binding affinity to human GFM1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0928	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	increases abundance, affects expression, affects cotreatment, decreases expression	3
bisphenol A	decreases expression, increases expression	2
Ozone	affects cotreatment, decreases expression, increases abundance, affects expression	2
Valproic Acid	increases expression, increases methylation	2
Cadmium Chloride	decreases expression, increases expression	2
Particulate Matter	increases expression, decreases expression, increases abundance	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	decreases expression	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
tebuconazole	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
bisphenol B	increases expression	1
bisphenol S	increases methylation	1
LDN 193189	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
Acetaminophen	decreases expression	1
Acrolein	decreases expression, increases abundance, affects cotreatment	1
Atrazine	decreases expression	1
Vehicle Emissions	increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation	1
Caffeine	decreases phosphorylation	1
Demecolcine	increases expression	1
Folic Acid	decreases expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Quercetin	decreases expression	1
Ribonucleotides	affects binding	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
CHEMBL5652905	Binding	Binding affinity to human GFM1 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 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_9U77	GFM1SV.25	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01721733	PHASE2	COMPLETED	Safety and Efficacy Study of EPI-743 in Children With Leigh Syndrome
NCT02352896	PHASE2	COMPLETED	Long-Term Safety and Efficacy Evaluation of EPI-743 in Children With Leigh Syndrome
NCT03747328	PHASE2	WITHDRAWN	ABI-009 (Nab-sirolimus) in Patients With Genetically-confirmed Leigh or Leigh-like Syndrome
NCT06843811	PHASE2	ENROLLING_BY_INVITATION	Sirolimus for Leigh Syndrome
NCT06990984	PHASE2	NOT_YET_RECRUITING	A Dose-ranging Study of TTI-0102 in Adults and Children With Leigh Syndrome Spectrum (LSS)
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT01780168	Not specified	RECRUITING	The NIH MINI Study: Metabolism, Infection, and Immunity in Inborn Errors of Metabolism
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01803906	Not specified	ENROLLING_BY_INVITATION	Tissue Sample Study for Mitochondrial Disorders
NCT03137355	Not specified	RECRUITING	The International Registry for Leigh Syndrome
NCT05277363	Not specified	WITHDRAWN	A Study of the Natural Course of SURF1 Deficiency
NCT05554835	Not specified	RECRUITING	Global Registry and Natural History Study for Mitochondrial Disorders
NCT06967831	Not specified	RECRUITING	Drug Repurposing for Mitochondrial Disorders Using iPSCs Derived Neural Cells