Human Gene Module / Chromosome 11 / EIF3F

EIF3Feukaryotic translation initiation factor 3 subunit F

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
4 / 6
Rare Variants / Common Variants
13 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
11p15.4
Associated Disorders
-
Relevance to Autism

The same homozygous missense variant in the EIF3F gene (c.694T>G;p.Phe232Val) was identified in two recently described individuals who were diagnosed with ASD and presented with additional neurodevelopmental comorbidities (Bar et al., 2024; Lob et al., 2024). The homozygous p.Phe232Val missense variant in EIF3F has previously been associated with an autosomal recessive neurodevelopmental disorder characterized by global developmental delay, intellectual disability, behavioral problems, and hearing loss (Martin et al., 2018; Huffmeier et al., 2021); autism or autistic behavior was reported in a subset of individuals. Martin et al., 2018 had additionally demonstrated in CRISPR-Cas9-edited iPSCs that cells homozygous for the p.Phe232Val variant displayed approximately 27% lower EIF3F protein levels and reduced proliferation rates relative to heterozygous and wild-type cells. De novo missense variants in the EIF3F gene have also been identified in ASD probands from the Autism Sequencing Consortium and the SPARK cohort (Satterstrom et al., 2020; Trost et al., 2022).

Molecular Function

Enables deubiquitinase activity and identical protein binding activity. Contributes to translation initiation factor activity. Involved in IRES-dependent viral translational initiation; protein deubiquitination; and translational initiation. Located in membrane. Part of eukaryotic translation initiation factor 3 complex.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to EIF3F (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support - Martin HC et al. (2018) No Epilepsy/seizures, autistic behavior
2 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
3 Support - Ulrike Hüffmeier et al. (2021) No ASD or autistic features, epilepsy/seizures
4 Support - Trost B et al. (2022) Yes -
5 Support - Omri Bar et al. (2024) Yes -
6 Primary - Karen Lob et al. () Yes DD
Rare Variants   (13)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.694T>G p.Phe232Val missense_variant Unknown - - 39136901 Karen Lob et al. ()
c.864A>T p.Gln288His missense_variant De novo - - 36368308 Trost B et al. (2022)
c.1048C>T p.Leu350Phe missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.694T>G p.Phe232Val missense_variant Unknown - Simplex 30409806 Martin HC et al. (2018)
c.694T>G p.Phe232Val missense_variant Unknown - Extended multiplex 38256266 Omri Bar et al. (2024)
c.694T>G p.Phe232Val missense_variant Unknown - Simplex 33736665 Ulrike Hüffmeier et al. (2021)
c.694T>G p.Phe232Val missense_variant Familial Both parents Simplex 30409806 Martin HC et al. (2018)
c.694T>G p.Phe232Val missense_variant Familial Both parents Multiplex 30409806 Martin HC et al. (2018)
c.694T>G p.Phe232Val missense_variant Familial Both parents - 33736665 Ulrike Hüffmeier et al. (2021)
c.694T>G p.Phe232Val missense_variant Familial Maternal Simplex 33736665 Ulrike Hüffmeier et al. (2021)
c.694T>G p.Phe232Val missense_variant Familial Both parents Simplex 33736665 Ulrike Hüffmeier et al. (2021)
c.694T>G p.Phe232Val missense_variant Familial Both parents Multiplex 33736665 Ulrike Hüffmeier et al. (2021)
c.861dup p.Gln288AlafsTer14 frameshift_variant Familial Paternal Simplex 33736665 Ulrike Hüffmeier et al. (2021)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

Score Delta: Score remained at 1

criteria met
See SFARI Gene'scoring criteria
3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

4/1/2022
icon
1

Increased from to 1

Krishnan Probability Score

Score 0.35541873442041

Ranking 24203/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.66906733755045

Ranking 4647/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.92617828840936

Ranking 10376/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score -0.20779389763354

Ranking 15594/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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