Human Gene Module / Chromosome 17 / PSMD12

PSMD12proteasome 26S subunit, non-ATPase 12

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
1 / 6
Rare Variants / Common Variants
14 / 0
EAGLE Score
6
Limited Learn More
Aliases
PSMD12, Rpn5,  p55
Associated Syndromes
Stankiewicz-Isidor syndrome
Chromosome Band
17q24.2
Associated Disorders
DD/NDD, ASD, EPS
Genetic Category
Rare Single Gene Mutation, Syndromic
Relevance to Autism

Six de novo deletions and four de novo loss-of-function point mutations in the PSMD12 gene were identified in unrelated individuals presenting with a syndromic neurodevelopmental disorder characterized by intellectual disability (Kury et al., 2017). Of the four individuals with de novo loss-of-function mutations, two were diagnosed with autism or autistic spectrum disorder (a proband from the Simons Simplex Collection and a case from Baylor Genetics Laboratories, respectively), while another individual from Boston Children's Hospital presented with autistic behavior.

Molecular Function

The protein encoded by this gene acts as a regulatory subunit of the 26S proteasome which is involved in the ATP-dependent degradation of ubiquitinated proteins.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PSMD12 (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder Kry S , et al. (2017) No Epilepsy/seizures, ASD or autistic features
2 Support Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands Jin SC , et al. (2017) No Neurodevelopmental disorders (NDD)
3 Support PSMD12 haploinsufficiency in a neurodevelopmental disorder with autistic features Khalil R , et al. (2018) No ASD or autistic features
4 Support - Zhou X et al. (2022) Yes -
5 Recent Recommendation - Timberlake AT et al. (2023) No ASD
6 Support - Axel Schmidt et al. (2024) No -
Rare Variants   (14)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 28132691 Kry S , et al. (2017)
- - copy_number_loss De novo - Simplex 28132691 Kry S , et al. (2017)
c.909-2A>G - splice_site_variant De novo - - 28132691 Kry S , et al. (2017)
c.1000G>T p.Glu334Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.163C>T p.Arg55Cys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1351A>G p.Met451Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.367C>T p.Arg123Ter stop_gained De novo - - 39039281 Axel Schmidt et al. (2024)
c.367C>T p.Arg123Ter stop_gained De novo - Simplex 28132691 Kry S , et al. (2017)
c.601C>T p.Arg201Ter stop_gained De novo - Simplex 28132691 Kry S , et al. (2017)
c.1274T>G p.Leu425Ter stop_gained De novo - Simplex 28132691 Kry S , et al. (2017)
c.601C>T p.Arg201Ter stop_gained De novo - Simplex 30421579 Khalil R , et al. (2018)
c.1091_1092del p.Asn364IlefsTer4 frameshift_variant De novo - - 28991257 Jin SC , et al. (2017)
c.367C>T p.Arg123Ter stop_gained Familial Paternal Multiplex 30421579 Khalil R , et al. (2018)
c.148_149del p.Leu50GlyfsTer26 frameshift_variant De novo - - 39039281 Axel Schmidt et al. (2024)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
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.

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."

10/1/2019
S
icon
1

Increased from S to 1

New Scoring Scheme
Description

Six de novo deletions and four de novo loss-of-function point mutations in the PSMD12 gene were identified in unrelated individuals presenting with a syndromic neurodevelopmental disorder characterized by intellectual disability (Kury et al., 2017). Of the four individuals with de novo loss-of-function mutations, two were diagnosed with autism or autistic spectrum disorder (a proband from the Simons Simplex Collection and a case from Baylor Genetics Laboratories, respectively), while another individual from Boston Children's Hospital presented with autistic behavior.

Reports Added
[New Scoring Scheme]
4/1/2019
S
icon
S

Increased from S to S

Description

Six de novo deletions and four de novo loss-of-function point mutations in the PSMD12 gene were identified in unrelated individuals presenting with a syndromic neurodevelopmental disorder characterized by intellectual disability (Kury et al., 2017). Of the four individuals with de novo loss-of-function mutations, two were diagnosed with autism or autistic spectrum disorder (a proband from the Simons Simplex Collection and a case from Baylor Genetics Laboratories, respectively), while another individual from Boston Children's Hospital presented with autistic behavior.

Reports Added
[PSMD12 haploinsufficiency in a neurodevelopmental disorder with autistic features.2018]
10/1/2017
S
icon
S

Increased from S to S

Description

Six de novo deletions and four de novo loss-of-function point mutations in the PSMD12 gene were identified in unrelated individuals presenting with a syndromic neurodevelopmental disorder characterized by intellectual disability (Kury et al., 2017). Of the four individuals with de novo loss-of-function mutations, two were diagnosed with autism or autistic spectrum disorder (a proband from the Simons Simplex Collection and a case from Baylor Genetics Laboratories, respectively), while another individual from Boston Children's Hospital presented with autistic behavior.

Reports Added
[Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands.2017]
Krishnan Probability Score

Score 0.49991183989514

Ranking 2120/25841 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 0.99726774215284

Ranking 1337/18225 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 0.11507965918734

Ranking 71/18665 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 -0.15820356665036

Ranking 14370/20870 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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