Human Gene Module / Chromosome 6 / CUL7

CUL7Cullin 7

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
8 / 8
Rare Variants / Common Variants
27 / 0
Aliases
CUL7, 3M1,  KIAA0076,  dJ20C7.5
Associated Syndromes
-
Chromosome Band
6p21.1
Associated Disorders
-
Relevance to Autism

Two de novo missense variants in the CUL7 gene have been identified in ASD probands from the Simons Simplex Collection, with no de novo events in this gene observed in 1,786 unaffected siblings (P=0.04) (Iossifov et al., 2014; Krumm et al., 2015). Furthermore, two inherited likely gene-disruptive variants in CUL7 were identified in simplex ASD probands with none observed in unaffected siblings (Krumm et al., 2015).

Molecular Function

The protein encoded by this gene is a component of an E3 ubiquitin-protein ligase complex that interacts with TP53, CUL9, and FBXW8 proteins. Defects in this gene are a cause of 3M syndrome type 1 (3M1).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CUL7 (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
3 Support De novo genic mutations among a Chinese autism spectrum disorder cohort Wang T , et al. (2016) Yes -
4 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
5 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
6 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
7 Support - Woodbury-Smith M et al. (2022) Yes -
8 Support - Zhou X et al. (2022) Yes -
Rare Variants   (27)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.3029G>C p.Arg1010Pro missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.244G>A p.Val82Met missense_variant De novo - - 31452935 Feliciano P et al. (2019)
c.1792C>T p.Gln598Ter stop_gained Familial Paternal - 27824329 Wang T , et al. (2016)
c.1900C>T p.Arg634Ter stop_gained Familial Paternal - 27824329 Wang T , et al. (2016)
c.839G>A p.Arg280Lys missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.4969C>T p.Arg1657Ter stop_gained Familial Maternal - 27824329 Wang T , et al. (2016)
c.4284T>C p.Leu1428= synonymous_variant De novo - - 31452935 Feliciano P et al. (2019)
c.2576T>C p.Leu859Pro missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.236G>A p.Arg79His missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.839G>A p.Arg280Gln missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.3575C>T p.Ala1192Val missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.1909G>A p.Ala637Thr missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.4129G>A p.Gly1377Ser missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.4129G>A p.Gly1377Ser missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.2120G>A p.Arg707His missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.4087C>G p.Leu1363Val missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.3381G>A p.Trp1127Ter stop_gained Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.4611G>A p.Trp1537Ter stop_gained Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.4969C>T p.Arg1657Ter stop_gained Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.4969C>T p.Arg1657Ter stop_gained Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.839G>A p.Arg280Gln missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.2681G>A p.Arg894Gln missense_variant Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.1644G>A p.Trp548Ter stop_gained Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.4943G>A p.Arg1648Gln missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.2166del p.Glu723SerfsTer31 frameshift_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.61_70del p.Val21ThrfsTer54 frameshift_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.3306del p.Arg1103AlafsTer122 frameshift_variant Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Two de novo missense variants in the CUL7 gene have been identified in ASD probands from the Simons Simplex Collection, with no de novo events in this gene observed in 1,786 unaffected siblings (P=0.04) (Iossifov et al., 2014; Krumm et al., 2015). Furthermore, two inherited likely gene-disruptive variants in CUL7 were identified in simplex ASD probands with none observed in unaffected siblings (Krumm et al., 2015).

Score Delta: Score remained at 2

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.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

Two de novo missense variants in the CUL7 gene have been identified in ASD probands from the Simons Simplex Collection, with no de novo events in this gene observed in 1,786 unaffected siblings (P=0.04) (Iossifov et al., 2014; Krumm et al., 2015). Furthermore, two inherited likely gene-disruptive variants in CUL7 were identified in simplex ASD probands with none observed in unaffected siblings (Krumm et al., 2015).

Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [New Scoring Scheme]
7/1/2019
3
icon
3

Decreased from 3 to 3

Description

Two de novo missense variants in the CUL7 gene have been identified in ASD probands from the Simons Simplex Collection, with no de novo events in this gene observed in 1,786 unaffected siblings (P=0.04) (Iossifov et al., 2014; Krumm et al., 2015). Furthermore, two inherited likely gene-disruptive variants in CUL7 were identified in simplex ASD probands with none observed in unaffected siblings (Krumm et al., 2015).

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
1/1/2019
3
icon
3

Decreased from 3 to 3

Description

Two de novo missense variants in the CUL7 gene have been identified in ASD probands from the Simons Simplex Collection, with no de novo events in this gene observed in 1,786 unaffected siblings (P=0.04) (Iossifov et al., 2014; Krumm et al., 2015). Furthermore, two inherited likely gene-disruptive variants in CUL7 were identified in simplex ASD probands with none observed in unaffected siblings (Krumm et al., 2015).

Reports Added
[Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.2018]
10/1/2016
3
icon
3

Decreased from 3 to 3

Description

Two de novo missense variants in the CUL7 gene have been identified in ASD probands from the Simons Simplex Collection, with no de novo events in this gene observed in 1,786 unaffected siblings (P=0.04) (Iossifov et al., 2014; Krumm et al., 2015). Furthermore, two inherited likely gene-disruptive variants in CUL7 were identified in simplex ASD probands with none observed in unaffected siblings (Krumm et al., 2015).

Reports Added
[De novo genic mutations among a Chinese autism spectrum disorder cohort.2016]
7/1/2015
icon
3

Increased from to 3

Description

Two de novo missense variants in the CUL7 gene have been identified in ASD probands from the Simons Simplex Collection, with no de novo events in this gene observed in 1,786 unaffected siblings (P=0.04) (Iossifov et al., 2014; Krumm et al., 2015). Furthermore, two inherited likely gene-disruptive variants in CUL7 were identified in simplex ASD probands with none observed in unaffected siblings (Krumm et al., 2015).

Krishnan Probability Score

Score 0.42059023604649

Ranking 21149/25841 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 2.2352565880124E-11

Ranking 17091/18225 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 0.94772368528894

Ranking 17392/18665 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 0.33929933141207

Ranking 2145/20870 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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