Human Gene Module / Chromosome 12 / USP15

USP15ubiquitin specific peptidase 15

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 4
Rare Variants / Common Variants
4 / 0
Aliases
USP15, UNPH-2,  UNPH4
Associated Syndromes
-
Chromosome Band
12q14.1
Associated Disorders
-
Relevance to Autism

Two de novo loss-of-function variants in the USP15 gene have been identified in ASD probands from simplex families (a frameshift variant in a Simons Simplex Collection proband in O'Roak et al., 2012; and a splice-site variant in a proband from a cohort of 116 ASD parent-proband trios as part of the University of Illinois at Chicago ACE project in Chen et al., 2017).

Molecular Function

This gene encodes a member of the ubiquitin specific protease (USP) family of deubiquitinating enzymes. USP enzymes play critical roles in ubiquitin-dependent processes through polyubiquitin chain disassembly and hydrolysis of ubiquitin-substrate bonds. The encoded protein associates with the COP9 signalosome, and also plays a role in transforming growth factor beta signalling through deubiquitination of receptor-activated SMAD transcription factors.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to USP15 (4 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 Recent Recommendation Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism Chen R , et al. (2017) Yes -
3 Support Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder Krupp DR , et al. (2017) Yes -
4 Support - Hu C et al. (2023) Yes -
Rare Variants   (4)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.348+9T>C - intron_variant Unknown - - 37007974 Hu C et al. (2023)
c.1473+1G>A - splice_site_variant De novo - Simplex 28344757 Chen R , et al. (2017)
c.813T>G p.Tyr271Ter stop_gained De novo - Simplex 28867142 Krupp DR , et al. (2017)
c.941_944del p.Thr314SerfsTer12 frameshift_variant De novo - Simplex 22495309 O'Roak BJ , et al. (2012)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Two de novo loss-of-function variants in the USP15 gene have been identified in ASD probands from simplex families (a frameshift variant in a Simons Simplex Collection proband in O'Roak et al., 2012; and a splice-site variant in a proband from a cohort of 116 ASD parent-proband trios as part of the University of Illinois at Chicago ACE project in Chen et al., 2017). A third de novo LoF variant in USP15 was identified as a mosaic mutation in an ASD proband from the Simons Simplex Collection in Krupp et al., 2017.

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
2
icon
2

Score remained at 2

New Scoring Scheme
Description

Two de novo loss-of-function variants in the USP15 gene have been identified in ASD probands from simplex families (a frameshift variant in a Simons Simplex Collection proband in O'Roak et al., 2012; and a splice-site variant in a proband from a cohort of 116 ASD parent-proband trios as part of the University of Illinois at Chicago ACE project in Chen et al., 2017). A third de novo LoF variant in USP15 was identified as a mosaic mutation in an ASD proband from the Simons Simplex Collection in Krupp et al., 2017.

Reports Added
[New Scoring Scheme]
10/1/2017
3
icon
2

Decreased from 3 to 2

Description

Two de novo loss-of-function variants in the USP15 gene have been identified in ASD probands from simplex families (a frameshift variant in a Simons Simplex Collection proband in O'Roak et al., 2012; and a splice-site variant in a proband from a cohort of 116 ASD parent-proband trios as part of the University of Illinois at Chicago ACE project in Chen et al., 2017). A third de novo LoF variant in USP15 was identified as a mosaic mutation in an ASD proband from the Simons Simplex Collection in Krupp et al., 2017.

Reports Added
[Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder.2017]
4/1/2017
icon
3

Increased from to 3

Description

Two de novo loss-of-function variants in the USP15 gene have been identified in ASD probands from simplex families (a frameshift variant in a Simons Simplex Collection proband in O'Roak et al., 2012; and a splice-site variant in a proband from a cohort of 116 ASD parent-proband trios as part of the University of Illinois at Chicago ACE project in Chen et al., 2017).

Krishnan Probability Score

Score 0.49086273668715

Ranking 5937/25841 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 0.99036501612574

Ranking 1791/18225 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 0.37654893511966

Ranking 251/18665 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 0.51210831939984

Ranking 425/20870 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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