EIF3F

Summary

EIF3F (eukaryotic translation initiation factor 3 subunit F, HGNC:3275) is a protein-coding gene on chromosome 11p15.4, encoding Eukaryotic translation initiation factor 3 subunit F (O00303). Component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which is required for several steps in the initiation of protein synthesis. It is a common-essential gene (DepMap: required in 97.7% of cancer cell lines).

Enables identical protein binding activity and metal-dependent deubiquitinase activity. Contributes to translation initiation factor activity. Involved in IRES-dependent viral translational initiation and translational initiation. Located in membrane. Part of eukaryotic translation initiation factor 3 complex. Implicated in autosomal recessive intellectual developmental disorder 67.

Source: NCBI Gene 8665 — RefSeq curated summary.

At a glance

• Gene–disease (curated): syndromic intellectual disability (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 11
• Clinical variants (ClinVar): 98 total — 2 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 23
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 97.7% of screened cell lines (common-essential)
• MANE Select transcript: NM_003754

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3275
Approved symbol	EIF3F
Name	eukaryotic translation initiation factor 3 subunit F
Location	11p15.4
Locus type	gene with protein product
Status	Approved
Aliases	eIF3-epsilon, eIF3-p47
Ensembl gene	ENSG00000175390
Ensembl biotype	protein_coding
OMIM	603914
Entrez	8665

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 7 retained_intron, 7 protein_coding, 5 nonsense_mediated_decay

ENST00000528653, ENST00000528763, ENST00000530219, ENST00000531329, ENST00000531572, ENST00000532882, ENST00000533626, ENST00000640290, ENST00000651655, ENST00000677121, ENST00000677179, ENST00000677795, ENST00000677866, ENST00000678132, ENST00000678993, ENST00000919670, ENST00000919671, ENST00000919672, ENST00000919673

RefSeq mRNA: 1 — MANE Select: NM_003754 NM_003754

CCDS: CCDS7785

Canonical transcript exons

ENST00000651655 — 8 exons

Exon	Start	End
ENSE00003471305	7992084	7992163
ENSE00003540585	7994982	7995118
ENSE00003630755	7995254	7995367
ENSE00003640631	7992887	7993024
ENSE00003643825	7994426	7994517
ENSE00003842985	7995945	8001852
ENSE00003889922	7987337	7987716
ENSE00003892116	7991781	7991851

Expression profiles

Bgee: expression breadth ubiquitous, 261 present calls, max score 99.65.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 178.7702 / max 992.4210, expressed in 1824 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
112929	178.0152	1824
206176	0.5533	267
206177	0.1572	49
112928	0.0445	21

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	99.65	gold quality
ganglionic eminence	UBERON:0004023	99.41	gold quality
left ovary	UBERON:0002119	99.38	gold quality
skin of leg	UBERON:0001511	99.31	gold quality
skin of abdomen	UBERON:0001416	99.30	gold quality
body of pancreas	UBERON:0001150	99.29	gold quality
ventricular zone	UBERON:0003053	99.28	gold quality
right ovary	UBERON:0002118	99.27	gold quality
stromal cell of endometrium	CL:0002255	99.20	gold quality
granulocyte	CL:0000094	99.18	gold quality
body of uterus	UBERON:0009853	99.18	gold quality
endocervix	UBERON:0000458	99.17	gold quality
mucosa of stomach	UBERON:0001199	99.16	gold quality
muscle layer of sigmoid colon	UBERON:0035805	99.16	gold quality
body of stomach	UBERON:0001161	99.14	gold quality
cortical plate	UBERON:0005343	99.09	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.03	gold quality
ectocervix	UBERON:0012249	99.00	gold quality
descending thoracic aorta	UBERON:0002345	98.99	gold quality
lower esophagus	UBERON:0013473	98.99	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.99	gold quality
lower esophagus mucosa	UBERON:0035834	98.99	gold quality
left uterine tube	UBERON:0001303	98.98	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.97	gold quality
right uterine tube	UBERON:0001302	98.92	gold quality
transverse colon	UBERON:0001157	98.91	gold quality
popliteal artery	UBERON:0002250	98.89	gold quality
tibial artery	UBERON:0007610	98.89	gold quality
small intestine Peyer’s patch	UBERON:0003454	98.86	gold quality
ascending aorta	UBERON:0001496	98.85	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-10042	yes	4.94
E-CURD-97	no	3069.75
E-MTAB-7606	no	667.29
E-MTAB-6379	no	644.91
E-HCAD-8	no	50.12
E-GEOD-125970	no	3.25
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

6 targeting EIF3F, 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-4302	99.89	67.94	1187
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-3164	99.02	68.39	1071
HSA-MIR-6820-3P	99.02	68.50	1035
HSA-MIR-134-5P	97.11	66.52	976
HSA-MIR-3118	97.11	66.58	984

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 97.7% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 15)

• Loss of EIF3F in pancreatic cancer is reported. (PMID:17918192)
• demonstrated a statistically significant decrease of the eIF3f gene copy number in melanoma compared with normal tissues with a tumor/normal ratio of 0.52 (PMID:18381585)
• eIF3f specifically interferes with the 3’ end processing of HIV-1 mRNAs (PMID:19237569)
• eIF3f may inhibit translation by increasing the binding to the eIF3 complex during apoptosis. (PMID:19245811)
• eIF3f mediates restriction of HIV-1 expression through a set of factors that includes eIF3f, the SR protein 9G8, and the cyclin-dependent kinase 11 (CDK11). (PMID:19854136)
• catalytically inactive forms of eIF3f as well as shRNAs targeting eIF3f repress Notch activation in a coculture assay, showing that eIF3f is a new positive regulator of the Notch pathway (PMID:21124883)
• findings established a new mechanism of rRNA decay regulation mediated by hnRNP K/eIF3f and suggest that the tumor suppressive function of eIF3f may link to impaired rRNA degradation and translation (PMID:22457825)
• Decreased expression of eukaryotic initiation factor 3f is associated with gastric cancer. (PMID:24678890)
• eIF3f may play an important role in recurrence. (PMID:24732644)
• eIF3f/alpha adrenergic receptor interaction (PMID:26497985)
• The overexpression of eIF3f suppressed Akt and ERK signaling and subsequently depleted CLU expression. In addition, eIF3F stabilized p53, which increased the expression of p21 and Bax. (PMID:26988917)
• results underscore the importance of estrogen-ERalpha-mediated control of eIF3f expression for the proliferation and survival of ER-positive breast cancer cells. These findings may provide rationale for the development of new therapies to treat ER-positive breast cancer. (PMID:30573685)
• Study discovered a role of EIF3F-STAT3 interaction in the genetic control of cell migration and metastasis in human lung adenocarcinoma. EIF3F promotes lung cancer cell metastasis in vivo by regulating a cluster of 34 metastasis-promoting genes including Snail2. The interaction between EIF3F and STAT3 controlled the EIF3F-mediated increase in Snail2 expression and cellular invasion. (PMID:31527668)
• EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum. (PMID:33736665)
• eIF3f Mediates SGOC Pathway Reprogramming by Enhancing Deubiquitinating Activity in Colorectal Cancer. (PMID:37544925)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	eif3f	ENSDARG00000077533
mus_musculus	Eif3f	ENSMUSG00000031029
rattus_norvegicus	Eif3f	ENSRNOG00000015221
drosophila_melanogaster	eIF3f2	FBGN0033069
drosophila_melanogaster	eIF3f1	FBGN0037270
caenorhabditis_elegans		WBGENE00001229

Paralogs (2): PSMD7 (ENSG00000103035), COPS6 (ENSG00000168090)

Protein

Protein identifiers

Eukaryotic translation initiation factor 3 subunit F — O00303 (reviewed: O00303)

Alternative names: Deubiquitinating enzyme eIF3f, Eukaryotic translation initiation factor 3 subunit 5, eIF-3-epsilon, eIF3 p47

All UniProt accessions (6): A0A1W2PP79, A0A7I2V4S2, A0A7I2YQA0, E9PQV8, O00303, H0YDT6

UniProt curated annotations — full annotation on UniProt →

Function. Component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which is required for several steps in the initiation of protein synthesis. The eIF-3 complex associates with the 40S ribosome and facilitates the recruitment of eIF-1, eIF-1A, eIF-2:GTP:methionyl-tRNAi and eIF-5 to form the 43S pre-initiation complex (43S PIC). The eIF-3 complex stimulates mRNA recruitment to the 43S PIC and scanning of the mRNA for AUG recognition. The eIF-3 complex is also required for disassembly and recycling of post-termination ribosomal complexes and subsequently prevents premature joining of the 40S and 60S ribosomal subunits prior to initiation. The eIF-3 complex specifically targets and initiates translation of a subset of mRNAs involved in cell proliferation, including cell cycling, differentiation and apoptosis, and uses different modes of RNA stem-loop binding to exert either translational activation or repression. Deubiquitinates activated NOTCH1, promoting its nuclear import, thereby acting as a positive regulator of Notch signaling.

Subunit / interactions. Component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which is composed of 13 subunits: EIF3A, EIF3B, EIF3C, EIF3D, EIF3E, EIF3F, EIF3G, EIF3H, EIF3I, EIF3J, EIF3K, EIF3L and EIF3M. The eIF-3 complex appears to include 3 stable modules: module A is composed of EIF3A, EIF3B, EIF3G and EIF3I; module B is composed of EIF3F, EIF3H, and EIF3M; and module C is composed of EIF3C, EIF3D, EIF3E, EIF3K and EIF3L. EIF3C of module C binds EIF3B of module A and EIF3H of module B, thereby linking the three modules. EIF3J is a labile subunit that binds to the eIF-3 complex via EIF3B. The eIF-3 complex interacts with RPS6KB1 under conditions of nutrient depletion. Mitogenic stimulation leads to binding and activation of a complex composed of MTOR and RPTOR, leading to phosphorylation and release of RPS6KB1 and binding of EIF4B to eIF-3. Interacts with RNF139; the interaction leads to protein translation inhibitions in a ubiquitination-dependent manner. Interacts with DTX1, the interaction is required for deubiquitinating activity towards NOTCH1.

Subcellular location. Cytoplasm.

Post-translational modifications. Phosphorylation is enhanced upon serum stimulation. Phosphorylated during apoptosis by caspase-processed CDK11.

Disease relevance. Intellectual developmental disorder, autosomal recessive 67 (MRT67) [MIM:618295] A form of intellectual disability, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Some MRT67 patients manifest seizures and sensorineural hearing loss. The disease may be caused by variants affecting the gene represented in this entry.

Domain organisation. The MPN domain mediates deubiquitinating activity.

Similarity. Belongs to the eIF-3 subunit F family.

RefSeq proteins (1): NP_003745* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000555	JAMM/MPN+_dom	Domain
IPR024969	EIF3F/CSN6-like_C	Domain
IPR027531	eIF3f	Family
IPR037518	MPN	Domain

Pfam: PF01398, PF13012

UniProt features (38 total): strand 12, helix 8, turn 4, modified residue 4, sequence variant 3, compositionally biased region 2, initiator methionine 1, chain 1, sequence conflict 1, domain 1, region of interest 1

Structure

Experimental structures (PDB)

27 structures.

PDB	Method	Resolution (Å)
8PPL	ELECTRON MICROSCOPY	2.65
6ZP4	ELECTRON MICROSCOPY	2.9
8PJ5	ELECTRON MICROSCOPY	2.9
8PJ6	ELECTRON MICROSCOPY	2.9
6ZON	ELECTRON MICROSCOPY	3
9KZU	ELECTRON MICROSCOPY	3
8PJ4	ELECTRON MICROSCOPY	3.2
9KN5	ELECTRON MICROSCOPY	3.2
9KRP	ELECTRON MICROSCOPY	3.2
6YBD	ELECTRON MICROSCOPY	3.3
9KKF	ELECTRON MICROSCOPY	3.3
9KN6	ELECTRON MICROSCOPY	3.3
9KZX	ELECTRON MICROSCOPY	3.3
8PJ1	ELECTRON MICROSCOPY	3.4
8PJ2	ELECTRON MICROSCOPY	3.4
8RG0	ELECTRON MICROSCOPY	3.4
7A09	ELECTRON MICROSCOPY	3.5
8OZ0	ELECTRON MICROSCOPY	3.5
8XXN	ELECTRON MICROSCOPY	3.6
6ZMW	ELECTRON MICROSCOPY	3.7
7QP7	ELECTRON MICROSCOPY	3.7
8PJ3	ELECTRON MICROSCOPY	3.7
6ZVJ	ELECTRON MICROSCOPY	3.8
9BLN	ELECTRON MICROSCOPY	3.9
7QP6	ELECTRON MICROSCOPY	4.7
3J8B	ELECTRON MICROSCOPY	9.3
3J8C	ELECTRON MICROSCOPY	11.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00303-F1	75.97	0.29

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 (4): 2, 46, 238, 258

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-156827	L13a-mediated translational silencing of Ceruloplasmin expression
R-HSA-72649	Translation initiation complex formation
R-HSA-72689	Formation of a pool of free 40S subunits
R-HSA-72695	Formation of the ternary complex, and subsequently, the 43S complex
R-HSA-72702	Ribosomal scanning and start codon recognition
R-HSA-72706	GTP hydrolysis and joining of the 60S ribosomal subunit

MSigDB gene sets: 288 (showing top): GOBP_CYTOPLASMIC_TRANSLATION, GOMF_METALLOPEPTIDASE_ACTIVITY, MODULE_151, ENK_UV_RESPONSE_KERATINOCYTE_UP, GCM_NPM1, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, HSIAO_HOUSEKEEPING_GENES, GOBP_TRANSLATIONAL_INITIATION, GOCC_EUKARYOTIC_TRANSLATION_INITIATION_FACTOR_3_COMPLEX, GOMF_TRANSLATION_INITIATION_FACTOR_ACTIVITY, MODULE_149, GOBP_TRANSLATION, GCM_PSME1, GCM_PPP1CC, MORF_CCNI

GO Biological Process (6): formation of cytoplasmic translation initiation complex (GO:0001732), translational initiation (GO:0006413), proteolysis (GO:0006508), IRES-dependent viral translational initiation (GO:0075522), cytoplasmic translational initiation (GO:0002183), translation (GO:0006412)

GO Molecular Function (11): translation initiation factor activity (GO:0003743), cysteine-type deubiquitinase activity (GO:0004843), translation initiation factor binding (GO:0031369), identical protein binding (GO:0042802), metal-dependent deubiquitinase activity (GO:0140492), protein binding (GO:0005515), peptidase activity (GO:0008233), cysteine-type peptidase activity (GO:0008234), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787), deubiquitinase activity (GO:0101005)

GO Cellular Component (8): cytosol (GO:0005829), eukaryotic translation initiation factor 3 complex (GO:0005852), membrane (GO:0016020), eukaryotic 43S preinitiation complex (GO:0016282), eukaryotic 48S preinitiation complex (GO:0033290), synapse (GO:0045202), eukaryotic translation initiation factor 3 complex, eIF3m (GO:0071541), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Cap-dependent Translation Initiation	4
Eukaryotic Translation Initiation	1
Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
translational initiation	3
cellular anatomical structure	3
protein metabolic process	2
deubiquitinase activity	2
protein binding	2
peptidase activity	2
cytoplasm	2
cytosolic small ribosomal subunit	2
cytosolic translation preinitiation complex	2
cytoplasmic translational initiation	1
protein-RNA complex assembly	1
formation of translation initiation ternary complex	1
translation	1
metabolic process	1
viral process	1
viral translation	1
cytoplasmic translation	1
peptidyltransferase activity	1
translational elongation	1
translational termination	1
macromolecule biosynthetic process	1
protein biosynthetic process	1
translation factor activity	1
cysteine-type peptidase activity	1
metallopeptidase activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
ubiquitin-like protein peptidase activity	1
protein-containing complex	1
cell junction	1
eukaryotic translation initiation factor 3 complex	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

3346 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EIF3F	EIF3E	P60228	991
EIF3F	EIF3B	P55884	984
EIF3F	EIF3D	O15371	982
EIF3F	EIF3H	O15372	976
EIF3F	EIF3C	Q99613	973
EIF3F	RHBDF2	Q6PJF5	950
EIF3F	EIF3K	Q9UBQ5	942
EIF3F	EIF3L	Q9Y262	936
EIF3F	EIF3J	O75822	895
EIF3F	EIF3M	Q7L2H7	887
EIF3F	EIF3G	O75821	868
EIF3F	EIF3I	Q13347	848
EIF3F	COPS5	Q92905	832
EIF3F	CDK19	Q9BWU1	734
EIF3F	EIF5	P55010	666

IntAct

400 interactions, top by confidence:

A	B	Type	Score
EIF3F	EIF3M	psi-mi:“MI:0915”(physical association)	0.960
EIF3M	EIF3F	psi-mi:“MI:0915”(physical association)	0.960
EIF3F	EIF3M	psi-mi:“MI:0407”(direct interaction)	0.960
EIF3M	EIF3F	psi-mi:“MI:0914”(association)	0.960
EIF3F	EIF3B	psi-mi:“MI:0914”(association)	0.920
EIF3B	EIF3F	psi-mi:“MI:0915”(physical association)	0.920
EIF3A	EIF3F	psi-mi:“MI:0915”(physical association)	0.910
EIF3A	EIF3F	psi-mi:“MI:0914”(association)	0.910
EIF3H	EIF3F	psi-mi:“MI:0914”(association)	0.890
EIF3F	EIF3H	psi-mi:“MI:0915”(physical association)	0.890
EIF3F	EIF3H	psi-mi:“MI:0407”(direct interaction)	0.890

BioGRID (541): EIF3F (Affinity Capture-MS), EIF3F (Affinity Capture-MS), EIF3F (Affinity Capture-MS), EIF3F (Affinity Capture-MS), EIF3F (Affinity Capture-MS), EIF3B (Affinity Capture-MS), EIF3K (Affinity Capture-MS), EIF3E (Affinity Capture-MS), EIF3A (Affinity Capture-MS), EIF3H (Affinity Capture-MS), EIF3CL (Affinity Capture-MS), EIF3C (Affinity Capture-MS), EIF3M (Affinity Capture-MS), EIF3L (Affinity Capture-MS), EIF3D (Affinity Capture-MS)

ESM2 similar proteins: A1CQB4, A1CQH7, A1CS06, A1D379, A1D3E1, A1D4X8, A2Q8R9, A2QQ10, A2QQA2, A4QT78, A4R0E5, A5A6I3, A6RQZ9, A7E7B3, A7EGK5, B0XQ55, B0XQB9, O00303, O04202, P0C7N6, Q0CCM5, Q0D1J4, Q0UMR2, Q0UTQ6, Q1DHB6, Q1DRC9, Q1DY54, Q2GZK0, Q2HGJ2, Q2U2J1, Q2UPM0, Q2URI8, Q4IJM4, Q4PI88, Q4R5B8, Q4WKD7, Q4WTA6, Q4WTH0, Q5BB47, Q5BDW0

Diamond homologs: A1CQH7, A1D3E1, A2QQ10, A3QVV1, A4R0E5, A5A6I3, A8PZS4, B0X2G0, B0XQ55, B3M123, B3P239, B4GDU3, B4I3S1, B4JGX4, B4KBI4, B4LZ60, B4NJR8, B4PUG5, B4QVL3, O00303, O04202, O43060, P0CO84, P0CO85, Q0CCM5, Q0UTQ6, Q1DRC9, Q1HR47, Q295I4, Q2HGJ2, Q2UPM0, Q4PI88, Q4R5B8, Q4WTH0, Q54C49, Q6C4H1, Q7QD36, Q9DCH4, Q9P748, Q9VN50

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
EIF3F	up-regulates	NOTCH1	deubiquitination
CDK11B	unknown	EIF3F	phosphorylation
EIF3F	up-regulates	NOTCH	deubiquitination
S	“down-regulates activity”	EIF3F	binding
CDK11B	down-regulates	EIF3F	phosphorylation
“Cullin 1-RBX1-Skp1”	“down-regulates quantity by destabilization”	EIF3F	binding
FBXO33	“down-regulates quantity by destabilization”	EIF3F	polyubiquitination
EIF3F	“form complex”	EIF3_complex	binding
CDK11B	“up-regulates activity”	EIF3F	phosphorylation
CyclinD3/CDK11B	“up-regulates activity”	EIF3F	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 98 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
Formation of the ternary complex, and subsequently, the 43S complex	14	49.5×	1e-18
Translation initiation complex formation	15	46.8×	1e-19
Ribosomal scanning and start codon recognition	15	46.8×	1e-19
Formation of a pool of free 40S subunits	14	25.7×	1e-14
L13a-mediated translational silencing of Ceruloplasmin expression	15	24.9×	2e-15
GTP hydrolysis and joining of the 60S ribosomal subunit	15	24.6×	2e-15

GO biological processes:

GO term	Partners	Fold	FDR
formation of cytoplasmic translation initiation complex	13	182.6×	2e-26
translational initiation	15	67.2×	8e-22
regulation of translational initiation	6	35.1×	3e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	2
Uncertain significance	53
Likely benign	20
Benign	8

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
1697326	NM_003754.3(EIF3F):c.861dup (p.Gln288fs)	Pathogenic
625559	GRCh37/hg19 11p15.5-15.3(chr11:193146-12643136)	Pathogenic
3359241	NM_003754.3(EIF3F):c.181C>T (p.Gln61Ter)	Likely pathogenic
988781	NM_003754.3(EIF3F):c.671C>T (p.Pro224Leu)	Likely pathogenic

SpliceAI

1374 predictions. Top by Δscore:

Variant	Effect	Δscore
11:7991779:A:AG	acceptor_gain	1.0000
11:7991780:G:GG	acceptor_gain	1.0000
11:7991852:G:GG	donor_gain	1.0000
11:7992080:TTAG:T	acceptor_loss	1.0000
11:7992159:GGCTG:G	donor_gain	1.0000
11:7992160:GCTG:G	donor_gain	1.0000
11:7992160:GCTGG:G	donor_gain	1.0000
11:7992161:CTGGT:C	donor_loss	1.0000
11:7992162:TGGT:T	donor_loss	1.0000
11:7992163:GGTAA:G	donor_loss	1.0000
11:7992164:G:GG	donor_gain	1.0000
11:7992165:TAAGT:T	donor_loss	1.0000
11:7992166:AA:A	donor_loss	1.0000
11:7992882:CACA:C	acceptor_loss	1.0000
11:7992884:CAGGT:C	acceptor_loss	1.0000
11:7992885:AGGT:A	acceptor_loss	1.0000
11:7992886:GGTAC:G	acceptor_gain	1.0000
11:7993014:GCC:G	donor_gain	1.0000
11:7993022:CAG:C	donor_loss	1.0000
11:7993024:GGT:G	donor_loss	1.0000
11:7993025:G:C	donor_loss	1.0000
11:7993026:T:G	donor_loss	1.0000
11:7993049:GGCA:G	donor_gain	1.0000
11:7994420:CCGCA:C	acceptor_loss	1.0000
11:7994421:CGCA:C	acceptor_loss	1.0000
11:7994422:GCA:G	acceptor_loss	1.0000
11:7994423:CA:C	acceptor_loss	1.0000
11:7994424:A:AG	acceptor_gain	1.0000
11:7994424:AG:A	acceptor_loss	1.0000
11:7994425:G:A	acceptor_loss	1.0000

AlphaMissense

2291 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:7987639:C:A	P96Q	1.000
11:7987653:T:C	S101P	1.000
11:7987657:T:A	I102N	1.000
11:7987662:G:C	D104H	1.000
11:7987663:A:T	D104V	1.000
11:7987675:G:C	R108T	1.000
11:7987675:G:T	R108I	1.000
11:7987676:A:C	R108S	1.000
11:7987676:A:T	R108S	1.000
11:7987677:C:A	R109S	1.000
11:7987678:G:C	R109P	1.000
11:7987696:G:C	R115P	1.000
11:7987698:G:C	V116L	1.000
11:7987699:T:A	V116D	1.000
11:7987702:T:A	I117N	1.000
11:7987702:T:G	I117S	1.000
11:7987704:G:A	G118R	1.000
11:7987704:G:C	G118R	1.000
11:7987704:G:T	G118W	1.000
11:7987705:G:A	G118E	1.000
11:7987705:G:T	G118V	1.000
11:7987708:C:T	T119I	1.000
11:7987711:T:A	L120Q	1.000
11:7987711:T:C	L120P	1.000
11:7987711:T:G	L120R	1.000
11:7987714:T:C	L121S	1.000
11:7987714:T:G	L121W	1.000
11:7987716:G:A	G122R	1.000
11:7987716:G:C	G122R	1.000
11:7991781:G:A	G122E	1.000

dbSNP variants (sampled 300 via entrez): RS1000913830 (11:7995757 G>A,C), RS1000975751 (11:7994961 C>A), RS1001029558 (11:7994734 C>T), RS1001074196 (11:7989549 T>A,G), RS1001303838 (11:8000178 G>A), RS1001328381 (11:8000796 G>A,T), RS1001364128 (11:7995696 C>T), RS1001572714 (11:7990499 G>A), RS1001802721 (11:7999867 T>G), RS1002086467 (11:7999561 A>C), RS1002193712 (11:8000435 C>G), RS1002245899 (11:7989954 C>T), RS1002305931 (11:7995596 A>G), RS1002579736 (11:7996409 A>T), RS1002640181 (11:7996940 G>A,T)

Disease associations

OMIM: gene MIM:603914 | disease phenotypes: MIM:618295, MIM:617755, MIM:180860

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual developmental disorder, autosomal recessive 67	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
syndromic intellectual disability	Definitive	AR

Mondo (5): intellectual developmental disorder, autosomal recessive 67 (MONDO:0032662), intellectual disability (MONDO:0001071), neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (MONDO:0060596), neurodevelopmental disorder (MONDO:0700092), Silver-Russell syndrome 1 (MONDO:0020796)

Orphanet (3): BPTF-related intellectual disability-facial dysmorphism-skeletal anomalies syndrome (Orphanet:686482), Silver-Russell syndrome (Orphanet:813), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

23 total (23 of 23 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000358	Posteriorly rotated ears
HP:0000407	Sensorineural hearing impairment
HP:0000486	Strabismus
HP:0000589	Coloboma
HP:0000639	Nystagmus
HP:0000709	Psychosis
HP:0000750	Delayed speech and language development
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001344	Absent speech
HP:0001763	Pes planus
HP:0002360	Sleep disturbance
HP:0002376	Developmental regression
HP:0002858	Meningioma
HP:0003577	Congenital onset
HP:0003593	Infantile onset
HP:0003623	Neonatal onset
HP:0004322	Short stature
HP:0025336	Delayed ability to sit
HP:0031936	Delayed ability to walk

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST000779_8	Depression (quantitative trait)	3.000000e-06
GCST005950_10	Body mass index x sex x age interaction (4df test)	6.000000e-11
GCST005951_51	Body mass index	8.000000e-11
GCST005953_4	Body mass index (age <50)	4.000000e-11
GCST010725_20	Malaria	4.000000e-69
GCST010725_33	Malaria	2.000000e-67
GCST010725_51	Malaria	1.000000e-55
GCST90002390_504	Mean corpuscular hemoglobin	4.000000e-11
GCST90002392_559	Mean corpuscular volume	1.000000e-16
GCST90002396_456	Mean reticulocyte volume	1.000000e-19
GCST90002397_562	Mean spheric corpuscular volume	1.000000e-18

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0004527	mean corpuscular hemoglobin
EFO:0010701	mean reticulocyte volume

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2062352 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects binding, increases reaction, decreases expression, increases expression	3
Cadmium Chloride	increases expression, affects localization, increases abundance	3
chloropicrin	affects expression, decreases expression	2
GSK-J4	increases expression	1
FR900359	affects phosphorylation	1
methylmercuric chloride	decreases expression	1
bisphenol A	affects cotreatment, increases methylation	1
deoxynivalenol	increases expression	1
sodium arsenate	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression	1
arsenite	affects binding, increases reaction	1
cobaltous chloride	increases expression	1
potassium chromate(VI)	increases expression	1
cupric oxide	decreases expression	1
epigallocatechin gallate	decreases expression	1
CGP 52608	affects binding, increases reaction	1
nickel acetate	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
clothianidin	decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
ICG 001	decreases expression	1
LDN 193189	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
Arsenic Trioxide	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Acetaminophen	increases expression	1
Benzo(a)pyrene	increases methylation	1
Cadmium	increases expression, increases abundance	1
Caffeine	decreases phosphorylation	1
Dactinomycin	increases secretion, affects cotreatment	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2065200	Binding	Binding affinity to EIF3F in human Jurkat cells at 150 uM followed by UV irradiation for 30 mins with Wood’s glass filtered medium pressure mercury arc light after cell lysis measured after denaturing wash by SDS-PAGE based pull down assay	Biotinylated quercetin as an intrinsic photoaffinity proteomics probe for the identification of quercetin target proteins. — Bioorg Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study