Human Gene Module / Chromosome 17 / PSMC5

PSMC5proteasome 26S subunit, ATPase 5

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
2 / 3
Rare Variants / Common Variants
8 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
17q23.3
Associated Disorders
-
Relevance to Autism

Yu et al., 2024 described a cohort of seven individuals (two of whom were from DECIPHER) with heterozygous variants in the PSMC5 gene and presenting with a neurodevelopmental disorder characterized by developmental delay, intellectual disability, and behavioral anomalies, including five individuals with autism spectrum disorder or autistic features; functional assessment of a recurrent p.Pro320Arg missense variant that was arose de novo in four individuals from this cohort (three of whom presenting with autism spectrum disorder) demonstrated impaired proteasome function by reduced association between the 19S regulatory particle and the 20S core particle. Three additional ASD probands (one from the Simons Simplex Collection, two from the SPARK cohort) were also found to have de novo missense variants in the PSMC5 gene that were predicted to be deleterious (REVEL > 0.5) and were either absent or very rare in both ExAC and gnomAD; one of the SPARK probands carried the functionally relevant p.Pro320Arg missense variant.

Molecular Function

The 26S proteasome is a multicatalytic proteinase complex with a highly ordered structure composed of 2 complexes, a 20S core and a 19S regulator. The 20S core is composed of 4 rings of 28 non-identical subunits; 2 rings are composed of 7 alpha subunits and 2 rings are composed of 7 beta subunits. The 19S regulator is composed of a base, which contains 6 ATPase subunits and 2 non-ATPase subunits, and a lid, which contains up to 10 non-ATPase subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. This gene encodes one of the ATPase subunits, a member of the triple-A family of ATPases which have a chaperone-like activity. In addition to participation in proteasome functions, this subunit may participate in transcriptional regulation since it has been shown t

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PSMC5 (3 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 Support - Zhou X et al. (2022) Yes -
3 Primary - Zhong-Qiu Yu et al. () No ASD or autistic features, ADHD
Rare Variants   (8)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.959C>G p.Pro320Arg missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1084G>A p.Val362Met missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.479A>C p.Glu160Ala missense_variant Unknown - - 38776958 Zhong-Qiu Yu et al. ()
c.959C>G p.Pro320Arg missense_variant De novo - - 38776958 Zhong-Qiu Yu et al. ()
c.205C>T p.Gln69Ter stop_gained De novo - Simplex 38776958 Zhong-Qiu Yu et al. ()
c.959C>G p.Pro320Arg missense_variant De novo - Simplex 38776958 Zhong-Qiu Yu et al. ()
c.973C>T p.Arg325Trp missense_variant De novo - Simplex 38776958 Zhong-Qiu Yu et al. ()
c.772C>T p.Arg258Trp missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

Score Delta: Score remained at 3

criteria met
See SFARI Gene'scoring criteria
3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

7/1/2024
icon
3

Increased from to 3

Krishnan Probability Score

Score 0.57105838642648

Ranking 831/25841 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 0.96957142539059

Ranking 2368/18225 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 0.68647976893482

Ranking 1076/18665 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 0.074692277465215

Ranking 6658/20870 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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