Human Gene Module / Chromosome 4 / CPZ

CPZcarboxypeptidase Z

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 5
Rare Variants / Common Variants
12 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
4p16.1
Associated Disorders
-
Relevance to Autism

De novo damaging missense variants (defined by CADD score 25) in the CPZ gene were identified in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (De Rubeis et al., 2014; Iossifov et al., 2014), while a third de novo damaging missense variant in this gene was observed in an ASD proband from the SPARK cohort (Feliciano et al., 2019). A meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA identified CPZ as an ASD candidate gene with a q-value 0.1.

Molecular Function

This gene encodes a member of the metallocarboxypeptidase family. This enzyme displays carboxypeptidase activity towards substrates with basic C-terminal residues. It is most active at neutral pH and is inhibited by active site-directed inhibitors of metallocarboxypeptidases.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CPZ (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Recent Recommendation Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
4 Support - Zhou X et al. (2022) Yes -
5 Support - Cirnigliaro M et al. (2023) Yes -
Rare Variants   (12)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.644G>A p.Arg215His missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1708C>T p.Arg570Trp missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1790G>A p.Arg597Lys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1727G>A p.Arg576His missense_variant De novo - - 31452935 Feliciano P et al. (2019)
c.1564C>T p.Arg522Trp missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.1460T>A p.Leu487His missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1842G>A p.Thr614%3D synonymous_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.1510C>T p.Arg504Trp missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.570C>A p.Tyr190Ter stop_gained Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.87del p.Gly30ValfsTer53 frameshift_variant Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.839dup p.Asn281GlnfsTer14 frameshift_variant Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.709+2T>C - splice_site_variant Familial Maternal Multiplex (monozygotic twins) 37506195 Cirnigliaro M et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

De novo damaging missense variants (defined by CADD score 25) in the CPZ gene were identified in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (De Rubeis et al., 2014; Iossifov et al., 2014), while a third de novo damaging missense variant in this gene was observed in an ASD proband from the SPARK cohort (Feliciano et al., 2019). A meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA identified CPZ as an ASD candidate gene with a q-value 0.1.

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.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

De novo damaging missense variants (defined by CADD score 25) in the CPZ gene were identified in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (De Rubeis et al., 2014; Iossifov et al., 2014), while a third de novo damaging missense variant in this gene was observed in an ASD proband from the SPARK cohort (Feliciano et al., 2019). A meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA identified CPZ as an ASD candidate gene with a q-value 0.1.

10/1/2019
icon
3

Increased from to 3

New Scoring Scheme
Description

De novo damaging missense variants (defined by CADD score 25) in the CPZ gene were identified in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium (De Rubeis et al., 2014; Iossifov et al., 2014), while a third de novo damaging missense variant in this gene was observed in an ASD proband from the SPARK cohort (Feliciano et al., 2019). A meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA identified CPZ as an ASD candidate gene with a q-value 0.1.

Reports Added
[New Scoring Scheme]
Krishnan Probability Score

Score 0.44728093531449

Ranking 13084/25841 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 4.5079953042948E-21

Ranking 18013/18225 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 0.2992038239353

Ranking 179/18665 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 -0.084901787563335

Ranking 11762/20870 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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