Human Gene Module / Chromosome 18 / SETBP1

SETBP1SET binding protein 1

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
6 / 13
Rare Variants / Common Variants
33 / 0
Aliases
SETBP1, SEB
Associated Syndromes
Schinzel-Giedion syndrome
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
18q12.3
Associated Disorders
ASD, ID
Relevance to Autism

A de novo LoF variant (frameshift) was identified in a simplex ASD case from the Simons Simplex Collection (O'Roak et al., 2012). More recently, eight loss-of-function variants, three of which were de novo in origin, were identified in patients from DD/ID cohorts; social difficulties and/or other behavioral difficulties were observed in four of these patients (Coe et al., 2014).

Molecular Function

The protein encoded by this gene has been shown to bind the SET nuclear oncogene, which is involved in DNA replication. Mutations in this gene are associated with Schinzel-Giedion midface retraction syndrome (SGMFS) [MIM:269150], a disorder characterized by severe mental retardation, distinctive facial features, and multiple congenital malformations including skeletal abnormalities, genitourinary and renal malformations, cardiac defects, as well as a higher-than-normal prevalence of tumors, notably neuroepithelial neoplasia.

Reports related to SETBP1 (13 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. O'Roak BJ , et al. (2012) Yes -
2 Support Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Rauch A , et al. (2012) No ASD
3 Recent Recommendation Refining analyses of copy number variation identifies specific genes associated with developmental delay. Coe BP , et al. (2014) No -
4 Support De novo mutations in moderate or severe intellectual disability. Hamdan FF , et al. (2014) No Microcephaly
5 Recent Recommendation Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
6 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
7 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) No Speech delay
8 Support High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing. Martnez F , et al. (2016) No ID
9 Support De novo genic mutations among a Chinese autism spectrum disorder cohort. Wang T , et al. (2016) Yes -
10 Support Clinical exome sequencing: results from 2819 samples reflecting 1000 families. Trujillano D , et al. (2016) No -
11 Support SETBP1 induces transcription of a network of development genes by acting as an epigenetic hub. Piazza R , et al. (2018) No -
12 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model. Guo H , et al. (2018) Yes -
13 Support Characterization of intellectual disability and autism comorbidity through gene panel sequencing. Aspromonte MC , et al. (2019) Yes -
Rare Variants   (33)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo NA - 25217958 Coe BP , et al. (2014)
c.1873C>T p.Arg625Ter stop_gained Unknown - Unknown 25217958 Coe BP , et al. (2014)
c.1876C>T p.Arg626Ter stop_gained Unknown - Unknown 25217958 Coe BP , et al. (2014)
c.1596G>A p.Trp532Ter stop_gained De novo NA Unknown 25217958 Coe BP , et al. (2014)
c.3032C>G p.Ser1011Ter stop_gained De novo NA Unknown 25217958 Coe BP , et al. (2014)
c.1774A>T p.Lys592Ter stop_gained De novo NA Simplex 23020937 Rauch A , et al. (2012)
c.2612T>C p.Ile871Thr missense_variant De novo NA - 27620904 Martnez F , et al. (2016)
c.1202G>A p.Arg401Gln missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.2717C>G p.Pro906Arg missense_variant De novo NA Simplex 25363768 Iossifov I et al. (2014)
c.1198G>A p.Val400Ile missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1553T>C p.Leu518Pro missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1877G>A p.Arg626Gln missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.39dup p.Gly14ArgfsTer49 frameshift_variant Unknown - Unknown 25217958 Coe BP , et al. (2014)
c.3299A>G p.His1100Arg missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3566G>A p.Arg1189Gln missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3689C>T p.Thr1230Ile missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2572G>A p.Glu858Lys missense_variant De novo NA Simplex 25363760 De Rubeis S , et al. (2014)
c.2602G>A p.Asp868Asn missense_variant De novo NA Simplex 27848944 Trujillano D , et al. (2016)
c.4027G>A p.Asp1343Asn missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.427del p.Arg143ValfsTer152 frameshift_variant Unknown - Unknown 25217958 Coe BP , et al. (2014)
c.1231del p.Leu411TrpfsTer33 frameshift_variant Unknown - Unknown 25217958 Coe BP , et al. (2014)
c.2464del p.Ile822TyrfsTer13 frameshift_variant De novo NA Unknown 25217958 Coe BP , et al. (2014)
c.2718dup p.Ser907ValfsTer44 frameshift_variant De novo NA Simplex 22495309 O'Roak BJ , et al. (2012)
c.1821del p.Ser608AlafsTer22 frameshift_variant De novo NA Simplex 25356899 Hamdan FF , et al. (2014)
c.1877G>A p.Arg626Gln missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2218G>A p.Glu740Lys missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2267C>T p.Pro756Leu missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3017A>G p.Tyr1006Cys missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3029C>T p.Thr1010Ile missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3460C>T p.His1154Tyr missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3962G>A p.Arg1321His missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2199_2203del p.Glu734AlafsTer19 frameshift_variant De novo NA - 31209962 Aspromonte MC , et al. (2019)
c.2561C>G p.Ser854Cys missense_variant De novo NA Simplex 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

A de novo LoF variant in the SETBP1 gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22495309). Loss-of-function variants in this gene have also been identified in patients with developmental delay/intellectual disability, many of whom present with social difficulties and/or other behavioral problems (PMID 25217958).

Score Delta: Score remained at 3

1

High Confidence

See all Category 1 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
1

Decreased from 3 to 1

New Scoring Scheme
Description

A de novo LoF variant in the SETBP1 gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22495309). Loss-of-function variants in this gene have also been identified in patients with developmental delay/intellectual disability, many of whom present with social difficulties and/or other behavioral problems (PMID 25217958).

Reports Added
[New Scoring Scheme]
7/1/2019
3
icon
3

Decreased from 3 to 3

Description

A de novo LoF variant in the SETBP1 gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22495309). Loss-of-function variants in this gene have also been identified in patients with developmental delay/intellectual disability, many of whom present with social difficulties and/or other behavioral problems (PMID 25217958).

1/1/2019
3
icon
3

Decreased from 3 to 3

Description

A de novo LoF variant in the SETBP1 gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22495309). Loss-of-function variants in this gene have also been identified in patients with developmental delay/intellectual disability, many of whom present with social difficulties and/or other behavioral problems (PMID 25217958).

7/1/2018
4.5 + acc2
icon
3

Decreased from 4.5 + acc2 to 3

Description

A de novo LoF variant in the SETBP1 gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22495309). Loss-of-function variants in this gene have also been identified in patients with developmental delay/intellectual disability, many of whom present with social difficulties and/or other behavioral problems (PMID 25217958).

4/1/2018
3
icon
4.5 + acc2

Increased from 3 to 4.5 + acc2

Description

3

10/1/2016
3
icon
3

Increased from 3 to 3

Description

A de novo LoF variant in the SETBP1 gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22495309). Loss-of-function variants in this gene have also been identified in patients with developmental delay/intellectual disability, many of whom present with social difficulties and/or other behavioral problems (PMID 25217958).

1/1/2016
3
icon
3

Increased from 3 to 3

Description

A de novo LoF variant in the SETBP1 gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22495309). Loss-of-function variants in this gene have also been identified in patients with developmental delay/intellectual disability, many of whom present with social difficulties and/or other behavioral problems (PMID 25217958).

10/1/2014
icon
3

Increased from to 3

Description

A de novo LoF variant in the SETBP1 gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22495309). Loss-of-function variants in this gene have also been identified in patients with developmental delay/intellectual disability, many of whom present with social difficulties and/or other behavioral problems (PMID 25217958).

Krishnan Probability Score

Score 0.49774287812693

Ranking 2338/25841 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.
ExAC Score

Score 0.99900292938104

Ranking 1066/18225 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
Sanders TADA Score

Score 0.89128171866151

Ranking 5613/18665 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).
Larsen Cumulative Evidence Score

Score 24

Ranking 84/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
LRRC37A11P leucine rich repeat containing 37, member A11, pseudogene Human Protein Binding 342666
NAP1L2 Nucleosome assembly protein 1-like 2 Mouse Protein Binding 17954 P51860
PLEKHF2 pleckstrin homology domain containing, family F (with FYVE domain) member 2 Human Protein Binding 79666 Q9H8W4
SPANXC SPANX family, member C Human Protein Binding 64663 Q8TAD1
SPANXD SPANX family, member D Human Protein Binding 64648 Q9BXN6
XAGE1D Human Protein Binding 9503
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