EIF3F

protein-coding

eukaryotic translation initiation factor 3 subunit F, the group of Eukaryotic translation initiation factor 3|JAMM/MPN+ metallopeptidase family

Gene summary

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. [provided by Alliance of Genome Resources, Jul 2025]

Previous symbols:

EIF3S5

MANE transcript

NM_003754.3

Inheritance

ClinVar variants

P:4U:60B:30

Top phenotype

Intellectual developmental disorder 67

gnomAD constraint

pLI —, LoF o/e 0.07

Max pathogenic AF

—

Genomic locus

chr11:7,970,251-8,001,862

External References & Databases

Ensembl (ENSG00000175390)

Transcript & Mutation Effects

hg38 • Region Span ~31.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, autosomal recessive 67LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0032662

Submitter: Labcorp Genetics (formerly Invitae)

syndromic intellectual disabilityDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0000508

Submitter: ClinGen

*EIF3F* was first reported in relation to autosomal recessive syndromic intellectual disability in 2018 (Martin et al., PMID: 30409806). *EIF3F* encodes an essential subunit of eIF3, the largest eukaryotic translation initiation factor, which plays a role in cell proliferation and growth, cell cycle control, differentiation, and apoptosis. At least 31 patients from 24 families have been reported with biallelic *EIF3F* variants; 30 of these patients were homozygous for the same p.Phe232Val missense variant, and 1 patient was compound heterozygous for the p.Phe232Val missense variant and a frameshift variant (PMIDs: 30409806, 33736665). Haplotype analyses suggested that p.Phe232Val is a founder variant (PMID: 33736665). The p.Phe232Val variant has a frequency of 0.16% in non-Finnish Europeans, and no homozygotes are observed in gnomAD (v4.0.0). The mechanism of pathogenicity appears to be loss of function. Affected individuals present with global developmental delay, motor and speech delays, and intellectual disability; variable features include hearing loss, dysmorphic facial features, abnormal behaviors, hypo- or hypertonia, ophthalmological abnormalities, and epilepsy (PMIDs: 30409806, 33736665). Induced pluripotent stem cells (iPSC) homozygous for the p.Phe232Val missense variant had ~27% lower EIF3F protein levels, and significantly reduced translation and proliferation rates compared to heterozygous and wild-type cells (PMID: 30409806). In summary, there is definitive evidence supporting the relationship between *EIF3F* and autosomal recessive syndromic intellectual disability. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on December 6, 2023 (SOP Version 9).

intellectual developmental disorder, autosomal recessive 67MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032662

Submitter: Ambry Genetics

intellectual developmental disorder, autosomal recessive 67STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032662

Submitter: G2P

intellectual developmental disorder, autosomal recessive 67STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032662

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Intellectual developmental disorder 67AR

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 30409806

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EIF3F variants in ClinVar

8 Conditions Cataloged

Inborn genetic diseasesTotal: 36

not providedTotal: 35

not specifiedTotal: 27

EIF3F-related disorderTotal: 15

Intellectual developmental disorder, autosomal recessive 67Total: 10

Neurodevelopmental disorderTotal: 1

Intellectual disabilityTotal: 1

Neurodevelopmental disorder with dysmorphic facies and distal limb anomaliesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003754.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	23 clinvar		24
missense		2 clinvar	54 clinvar	6 clinvar	1 clinvar	63
nonsense		1 clinvar	1 clinvar			2
start loss						0
frameshift	1 clinvar		1 clinvar			2
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	1	3	60	29	1	94

Highest pathogenic variant AF is 0.0012514931

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 23 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003754.3	RefSeq	NP_003745.1	8	MANE Select
ENST00000651655.1	Ensembl	ENSP00000499218.1	8	MANE Select
ENST00000531329.6	Ensembl	ENSP00000432489.2	4	Standard
ENST00000531572.2	Ensembl	ENSP00000434286.2	7	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
eif3f	Danio rerio	Structure: pharyngeal arch cartilage Quality: malformed abnormal

Gene / Model

Organism

Observed Phenotype

eif3f

Danio rerio

Structure: pharyngeal arch cartilage

Quality: malformed

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

RNA transport - Homo sapiens (human)
Translation Factors
Formation of the ternary complex, and subsequently, the 43S complex
Translation initiation complex formation
Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S

Biological Process

formation of cytoplasmic translation initiation complex
translational initiation
protein deubiquitination
IRES-dependent viral translational initiation

Molecular Function

translation initiation factor activity
thiol-dependent ubiquitin-specific protease activity
protein binding
translation initiation factor binding

Cellular Component

cytosol
eukaryotic translation initiation factor 3 complex
membrane
eukaryotic 43S preinitiation complex
eukaryotic 48S preinitiation complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000533626
Coding exons: 8
Length: 31612
Individuals with no LoFs: 125747
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 125748
p: 0.00000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.108	212	208	1.02	0.0000109	2268
Missense (PolyPhen)		31	48.671	0.63692		632
Synonymous	-2.24	113	86.5	1.31	0.00000503	768
Loss of Function	3.39	1	15.3	0.0654	7.38e-7	181

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000088	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which is required for several steps in the initiation of protein synthesis (PubMed:17581632, PubMed:25849773, PubMed:27462815). 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 (PubMed:17581632). 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 (PubMed:25849773). {ECO:0000255|HAMAP-Rule:MF_03005, ECO:0000269|PubMed:17581632, ECO:0000269|PubMed:25849773, ECO:0000269|PubMed:27462815}.;

Recessive Scores

pRec: 0.112

Intolerance Scores

LoFtool: 0.435
RVIS EVS: -0.29
RVIS percentile EVS: 33.2

Essentials

Essential (CRISPR): E
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.806

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium