Human Gene Module / Chromosome 2 / FBXO11

FBXO11F-box protein 11

SFARI Gene Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
6 / 14
Rare Variants / Common Variants
84 / 0
Aliases
FBXO11, FBX11,  PRMT9,  UBR6,  UG063H01,  VIT1
Associated Syndromes
-
Chromosome Band
2p16.3
Associated Disorders
ASD, EPS
Relevance to Autism

Rare de novo variants (one loss-of-function, one damaging missense) were identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2012; Iossifov et al., 2014). Gregor et al., 2018 reported 20 individuals with de novo FBXO11 variants presenting with a variable neurodevelopmental disorder; behavioral abnormalities (including ASD or autistic features) were observed in 17/20 cases.

Molecular Function

This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbxs class. It can function as an arginine methyltransferase that symmetrically dimethylates arginine residues, and it acts as an adaptor protein to mediate the neddylation of p53, which leads to the suppression of p53 function.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to FBXO11 (14 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Primary Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
3 Support De novo FBXO11 mutations are associated with intellectual disability and behavioural anomalies Fritzen D , et al. (2018) No Behavioral abnormalities, microcephaly
4 Recent Recommendation De Novo Variants in the F-Box Protein FBXO11 in 20 Individuals with a Variable Neurodevelopmental Disorder Gregor A , et al. (2018) No ASD or autistic features, epilepsy/seizures
5 Support De novo variants in FBXO11 cause a syndromic form of intellectual disability with behavioral problems and dysmorphisms Jansen S , et al. (2019) No ASD or autistic features
6 Support Identification of De Novo JAK2 and MAPK7 Mutations Related to Autism Spectrum Disorder Using Whole-Exome Sequencing in a Chinese Child and Adolescent Trio-Based Sample Jiao J , et al. (2019) Yes -
7 Recent Recommendation - Gregor A et al. (2021) No ASD or autistic features, stereotypy, ADHD, epilep
8 Support - Woodbury-Smith M et al. (2022) Yes -
9 Support - Krgovic D et al. (2022) Yes DD
10 Support - Zhou X et al. (2022) Yes -
11 Support - Spataro N et al. (2023) No ASD, ADHD, epilepsy/seizures
12 Support - Sanchis-Juan A et al. (2023) No -
13 Support - Xin Pan et al. () No Epilepsy/seizures
14 Support - Axel Schmidt et al. (2024) No ID, cognitive impairment, epilepsy/seizures, stere
Rare Variants   (84)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 34505148 Gregor A et al. (2021)
- - copy_number_loss De novo - - 30057029 Gregor A , et al. (2018)
- - copy_number_loss De novo - - 30679813 Jansen S , et al. (2019)
- - copy_number_loss Familial Maternal Simplex 38740982 Xin Pan et al. ()
c.2338+1G>A - splice_site_variant De novo - - 34505148 Gregor A et al. (2021)
c.1042-1G>C - splice_site_variant De novo - - 30057029 Gregor A , et al. (2018)
c.1260+1G>C - splice_site_variant De novo - - 30057029 Gregor A , et al. (2018)
c.2084-1G>A - splice_site_variant De novo - - 30057029 Gregor A , et al. (2018)
c.1798-1G>A - splice_site_variant De novo - - 30679813 Jansen S , et al. (2019)
c.196C>T p.Pro66Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.550-1G>A - splice_site_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.660G>A p.Gln220%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.412A>G p.Arg138Gly missense_variant De novo - - 34505148 Gregor A et al. (2021)
c.554G>A p.Arg185His missense_variant De novo - - 34505148 Gregor A et al. (2021)
c.617A>G p.Tyr206Cys missense_variant De novo - - 34505148 Gregor A et al. (2021)
c.1733C>G p.Thr578Arg missense_variant De novo - - 34505148 Gregor A et al. (2021)
c.1949A>C p.His650Pro missense_variant De novo - - 34505148 Gregor A et al. (2021)
c.588-2A>G - splice_site_variant De novo - Simplex 34505148 Gregor A et al. (2021)
c.414A>T p.Arg138Ser missense_variant De novo - - 30057029 Gregor A , et al. (2018)
c.467A>G p.Gln156Arg missense_variant De novo - - 30057029 Gregor A , et al. (2018)
c.606A>C p.Glu202Asp missense_variant De novo - - 30679813 Jansen S , et al. (2019)
c.1797+1G>A - splice_site_variant De novo - Simplex 34505148 Gregor A et al. (2021)
c.1612A>G p.Ile538Val missense_variant De novo - - 30057029 Gregor A , et al. (2018)
c.1868C>G p.Thr623Arg missense_variant De novo - - 30057029 Gregor A , et al. (2018)
c.2518T>C p.Ser840Pro missense_variant De novo - - 30057029 Gregor A , et al. (2018)
c.2675C>A p.Ala892Asp missense_variant De novo - - 30057029 Gregor A , et al. (2018)
c.2714C>G p.Pro905Arg missense_variant De novo - - 30057029 Gregor A , et al. (2018)
c.2729A>G p.Asp910Gly missense_variant De novo - - 30057029 Gregor A , et al. (2018)
c.1517A>G p.Tyr506Cys missense_variant De novo - - 30679813 Jansen S , et al. (2019)
c.1660T>G p.Phe554Val missense_variant De novo - - 30679813 Jansen S , et al. (2019)
c.1781A>G p.His594Arg missense_variant De novo - - 30679813 Jansen S , et al. (2019)
c.1830T>G p.Asn610Lys missense_variant De novo - - 30679813 Jansen S , et al. (2019)
c.1967A>G p.Asn656Ser missense_variant De novo - - 30679813 Jansen S , et al. (2019)
c.2060G>A p.Gly687Asp missense_variant De novo - - 30679813 Jansen S , et al. (2019)
c.2074T>A p.Tyr692Asn missense_variant De novo - - 30679813 Jansen S , et al. (2019)
c.2145G>C p.Lys715Asn missense_variant De novo - - 30679813 Jansen S , et al. (2019)
c.1112G>T p.Ser371Ile missense_variant Unknown - - 35813072 Krgovic D et al. (2022)
c.1340G>C p.Arg447Thr missense_variant De novo - - 36980980 Spataro N et al. (2023)
c.1616G>A p.Arg539Lys missense_variant Unknown - Simplex 38740982 Xin Pan et al. ()
c.2224C>T p.Arg742Ter stop_gained De novo - Simplex 34505148 Gregor A et al. (2021)
c.442+1dup - splice_site_variant De novo - Simplex 29796876 Fritzen D , et al. (2018)
c.2709dup p.Glu904Ter frameshift_variant De novo - - 30057029 Gregor A , et al. (2018)
c.1648G>C p.Gly550Arg missense_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.1936G>A p.Gly646Arg missense_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.2729A>G p.Asp910Gly missense_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.1711T>A p.Leu571Ile missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.40G>T p.Val14Leu stop_gained Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.2335G>A p.Ala779Thr missense_variant De novo - Simplex 31838722 Jiao J , et al. (2019)
c.404A>G p.Lys135Arg missense_variant De novo - Simplex 34505148 Gregor A et al. (2021)
c.2395_2397del p.Asn799del inframe_deletion De novo - - 30679813 Jansen S , et al. (2019)
c.2570_2572del p.Asn857del inframe_deletion De novo - - 30679813 Jansen S , et al. (2019)
c.290G>A p.Ser97Asn missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.2075A>T p.Tyr692Phe missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.1261G>A p.Gly421Arg missense_variant De novo - Simplex 34505148 Gregor A et al. (2021)
c.1504A>C p.Thr502Pro missense_variant De novo - Simplex 34505148 Gregor A et al. (2021)
c.1645G>A p.Gly549Arg missense_variant De novo - Simplex 34505148 Gregor A et al. (2021)
c.1648G>C p.Gly550Arg missense_variant De novo - Simplex 34505148 Gregor A et al. (2021)
c.2036A>G p.Asn679Ser missense_variant De novo - Simplex 34505148 Gregor A et al. (2021)
c.2125A>G p.Met709Val missense_variant De novo - Simplex 34505148 Gregor A et al. (2021)
c.2729A>T p.Asp910Val missense_variant De novo - Simplex 34505148 Gregor A et al. (2021)
c.1825_1829del p.Glu609Ter frameshift_variant De novo - - 30057029 Gregor A , et al. (2018)
c.2738_2739del p.Tyr913Ter frameshift_variant De novo - - 30057029 Gregor A , et al. (2018)
c.2685_2686del p.Ser896Ter frameshift_variant De novo - - 30679813 Jansen S , et al. (2019)
c.2738_2739del p.Tyr913Ter frameshift_variant De novo - - 30679813 Jansen S , et al. (2019)
c.2697T>A p.Cys899Ter stop_gained Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.1981_1983del p.His661del inframe_deletion Unknown - Multiplex 38740982 Xin Pan et al. ()
c.552del p.Lys184AsnfsTer27 frameshift_variant De novo - - 30679813 Jansen S , et al. (2019)
c.668del p.Pro223GlnfsTer23 frameshift_variant De novo - - 30679813 Jansen S , et al. (2019)
c.2084-5_2084-4insTATAGGTT - frameshift_variant De novo - - 30057029 Gregor A , et al. (2018)
c.503_505del p.Phe168del inframe_deletion De novo - Simplex 34505148 Gregor A et al. (2021)
c.506_507del p.Ser169LeufsTer9 frameshift_variant De novo - - 30057029 Gregor A , et al. (2018)
c.147_182del p.Gln50_Pro61del inframe_deletion De novo - Simplex 35982159 Zhou X et al. (2022)
c.319_320del p.Leu107AlafsTer45 frameshift_variant De novo - - 30057029 Gregor A , et al. (2018)
c.191_199dup p.Pro64_Pro66dup inframe_insertion De novo - - 39039281 Axel Schmidt et al. (2024)
c.2520_2521del p.Ser841LeufsTer8 frameshift_variant De novo - - 30679813 Jansen S , et al. (2019)
c.2592_2593del p.Ile864MetfsTer6 frameshift_variant De novo - - 30679813 Jansen S , et al. (2019)
c.1696del p.Ile566PhefsTer6 frameshift_variant De novo - Simplex 34505148 Gregor A et al. (2021)
c.2568_2572del p.Asn857HisfsTer12 frameshift_variant De novo - - 30679813 Jansen S , et al. (2019)
c.2738_2739del p.Tyr913Ter frameshift_variant De novo - Simplex 29796876 Fritzen D , et al. (2018)
c.2700_2701insATTA p.Leu901IlefsTer5 frameshift_variant De novo - - 30057029 Gregor A , et al. (2018)
c.1571del p.Asn524ThrfsTer15 frameshift_variant Familial Maternal Multiplex 38740982 Xin Pan et al. ()
c.2745_2746del p.Ala916SerfsTer6 frameshift_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.2541_2551del p.Met847IlefsTer7 frameshift_variant Familial Maternal Simplex 38740982 Xin Pan et al. ()
c.2732_2738del p.Thr911MetfsTer7 frameshift_variant Unknown Not paternal - 36980980 Spataro N et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

Rare de novo variants (one loss-of-function, one damaging missense) were identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2012; Iossifov et al., 2014). Gregor et al., 2018 reported 20 individuals with de novo FBXO11 variants presenting with a variable neurodevelopmental disorder; behavioral abnormalities (including ASD or autistic features) were observed in 17/20 cases. Jansen et al., 2019 described 24 individuals with de novo FBXO11 variants (including the two ASD probands from the Simons Simplex Collection reported in Iossifov et al., 2012 and Iossifov et al., 2014) and found that behavioral problems were observed in 16 individuals (67%), with ASD or autistic features present in 7 individuals.

Score Delta: Score remained at 2S

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2022
3S
icon
2S

Decreased from 3S to 2S

Description

Rare de novo variants (one loss-of-function, one damaging missense) were identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2012; Iossifov et al., 2014). Gregor et al., 2018 reported 20 individuals with de novo FBXO11 variants presenting with a variable neurodevelopmental disorder; behavioral abnormalities (including ASD or autistic features) were observed in 17/20 cases. Jansen et al., 2019 described 24 individuals with de novo FBXO11 variants (including the two ASD probands from the Simons Simplex Collection reported in Iossifov et al., 2012 and Iossifov et al., 2014) and found that behavioral problems were observed in 16 individuals (67%), with ASD or autistic features present in 7 individuals.

1/1/2020
3S
icon
3S

Decreased from 3S to 3S

Description

Rare de novo variants (one loss-of-function, one damaging missense) were identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2012; Iossifov et al., 2014). Gregor et al., 2018 reported 20 individuals with de novo FBXO11 variants presenting with a variable neurodevelopmental disorder; behavioral abnormalities (including ASD or autistic features) were observed in 17/20 cases. Jansen et al., 2019 described 24 individuals with de novo FBXO11 variants (including the two ASD probands from the Simons Simplex Collection reported in Iossifov et al., 2012 and Iossifov et al., 2014) and found that behavioral problems were observed in 16 individuals (67%), with ASD or autistic features present in 7 individuals.

Reports Added
[Identification of De Novo JAK2 and MAPK7 Mutations Related to Autism Spectrum Disorder Using Whole-Exome Sequencing in a Chinese Child and Adolesce...2019]
10/1/2019
4S
icon
3S

Decreased from 4S to 3S

New Scoring Scheme
Description

Rare de novo variants (one loss-of-function, one damaging missense) were identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2012; Iossifov et al., 2014). Gregor et al., 2018 reported 20 individuals with de novo FBXO11 variants presenting with a variable neurodevelopmental disorder; behavioral abnormalities (including ASD or autistic features) were observed in 17/20 cases. Jansen et al., 2019 described 24 individuals with de novo FBXO11 variants (including the two ASD probands from the Simons Simplex Collection reported in Iossifov et al., 2012 and Iossifov et al., 2014) and found that behavioral problems were observed in 16 individuals (67%), with ASD or autistic features present in 7 individuals.

Reports Added
[New Scoring Scheme]
7/1/2018
icon
4S

Increased from to 4S

Description

Rare de novo variants (one loss-of-function, one damaging missense) were identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2012; Iossifov et al., 2014). Gregor et al., 2018 reported 20 individuals with de novo FBXO11 variants presenting with a variable neurodevelopmental disorder; behavioral abnormalities (including ASD or autistic features) were observed in 17/20 cases.

Krishnan Probability Score

Score 0.56801744202299

Ranking 1143/25841 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 0.99997962831639

Ranking 508/18225 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 0.15029437483321

Ranking 86/18665 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 0.49482765123696

Ranking 560/20870 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
CNVs associated with FBXO11(1 CNVs)
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2p16.3 88 Deletion-Duplication 131  /  545
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