Human Gene Module / Chromosome 4 / PPP3CA

PPP3CAprotein phosphatase 3 catalytic subunit alpha

SFARI Gene Score
3S
Suggestive Evidence, Syndromic Criteria 3.1, Syndromic
Autism Reports / Total Reports
3 / 13
Rare Variants / Common Variants
28 / 0
Aliases
PPP3CA, ACCIID,  CALN,  CALNA,  CALNA1,  CCN1,  CNA1,  DEE91,  IECEE,  IECEE1,  PPP2B
Associated Syndromes
-
Chromosome Band
4q24
Associated Disorders
ASD, EPS
Relevance to Autism

Autistic features and/or stereotypy has been observed in a subset of individuals with both PPP3CA-associated disorders (Myers et al., 2017; Mizuguchi et al., 2018; Panneerselvam et al., 2021). Genotype-phenotype correlation of 5 novel patients and 16 previously unpublished patients with PPP3CA variants in Panneerselvam et al., 2021 found that while autistic features were overall a commonly observed phenotype in individuals with PPP3CA variants (11/20, 55%), they were more frequently observed in individuals with missense variants in the catalytic domain (7/9, 78%) or the auto-inhibitory domain (2/3, 67%) of PPP3CA compared to individuals with truncating variants in the regulatory domain of the protein (1/7, 14%). Mizuguchi et al., 2018 had previously shown that missense variants in the catalytic domain of PPP3CA exhibit loss-of-function properties, whereas missense variants in the auto-inhibitory domain display gain-of-function properties. A rare de novo missense variant in PPP3CA has also been identified in an ASD proband from the Autism Sequencing Consortium in Satterstrom et al., 2020.

Molecular Function

The protein encoded by the PPP3CA gene is a calcium-dependent, calmodulin-stimulated protein phosphatase which plays an essential role in the transduction of intracellular Ca2+-mediated signals. Heterozygous variants in this gene are responsible for two distinct disorders: arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development (ACCIID; OMIM 618265), and developmental and epileptic encephalopathy-91 (DEE91; OMIM 617711).

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
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SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PPP3CA (13 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary - Myers CT et al. (2017) No Autistic features, stereotypy
2 Support - Mizuguchi T et al. (2018) No Autistic features, stereotypy
3 Support - Rydzanicz M et al. (2019) No -
4 Support - Qian Y et al. (2018) No -
5 Support - Li J et al. (2019) No -
6 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
7 Support - Yang S et al. (2020) No -
8 Recent Recommendation - Panneerselvam S et al. (2021) No ASD or autistic features, epilepsy/seizures
9 Support - Mahjani B et al. (2021) Yes -
10 Support - Zhou X et al. (2022) Yes -
11 Support - Ko YJ et al. (2023) No -
12 Support - Lucie Sedlackova et al. (2024) No -
13 Support - Erica Rosina et al. (2024) No -
Rare Variants   (28)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1333C>T p.Gln445Ter stop_gained De novo - - 28942967 Myers CT et al. (2017)
c.844G>A p.Glu282Lys missense_variant Unknown - - 37645600 Ko YJ et al. (2023)
c.278G>A p.Gly93Glu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.762G>C p.Arg254Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.275A>G p.His92Arg missense_variant De novo - - 28942967 Myers CT et al. (2017)
c.843C>G p.His281Gln missense_variant De novo - - 28942967 Myers CT et al. (2017)
c.844G>A p.Glu282Lys missense_variant De novo - - 28942967 Myers CT et al. (2017)
c.1339G>A p.Ala447Thr missense_variant De novo - - 28942967 Myers CT et al. (2017)
c.1456C>T p.Arg486Cys missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.1324C>T p.Gln442Ter stop_gained De novo - Simplex 30254215 Rydzanicz M et al. (2019)
c.1340-1G>C - splice_site_variant De novo - Simplex 38041506 Erica Rosina et al. (2024)
c.1533C>G p.Asp511Glu missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.760A>G p.Arg254Gly missense_variant De novo - - 33963760 Panneerselvam S et al. (2021)
c.844G>A p.Glu282Lys missense_variant De novo - - 33963760 Panneerselvam S et al. (2021)
c.1417G>T p.Ala473Ser missense_variant De novo - - 33963760 Panneerselvam S et al. (2021)
c.275A>G p.His92Arg missense_variant De novo - Simplex 29432562 Mizuguchi T et al. (2018)
c.702C>G p.Asp234Glu missense_variant De novo - Simplex 29432562 Mizuguchi T et al. (2018)
c.1408T>G p.Phe470Val missense_variant De novo - Simplex 29432562 Mizuguchi T et al. (2018)
c.1417G>A p.Ala473Thr missense_variant De novo - Simplex 29432562 Mizuguchi T et al. (2018)
c.1283dup p.Thr429AsnfsTer22 frameshift_variant De novo - Simplex 30904718 Li J et al. (2019)
c.1283insC p.Thr429AsnfsTer22 frameshift_variant De novo - Simplex 32593294 Yang S et al. (2020)
c.1299dup p.Ser434GlnfsTer17 frameshift_variant De novo - - 33963760 Panneerselvam S et al. (2021)
c.1268_1271dup p.Lys424AsnfsTer28 frameshift_variant De novo - Simplex 37645600 Ko YJ et al. (2023)
c.1255_1256del p.Ser419CysfsTer31 frameshift_variant De novo - Simplex 30455226 Qian Y et al. (2018)
c.1290dup p.Met431HisfsTer20 frameshift_variant De novo - Simplex 29432562 Mizuguchi T et al. (2018)
c.449A>T p.Asn150Ile missense_variant Unknown Not maternal Simplex 29432562 Mizuguchi T et al. (2018)
c.1255_1256del p.Ser419CysfsTer31 frameshift_variant De novo - - 38008000 Lucie Sedlackova et al. (2024)
c.1308_1309insACTT p.Leu437ThrfsTer15 frameshift_variant De novo - - 33963760 Panneerselvam S et al. (2021)
Common Variants  

No common variants reported.

SFARI Gene score
3S

Suggestive Evidence, Syndromic

Score Delta: Score remained at 3S

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.

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."

4/1/2022
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3S

Increased from to 3S

Krishnan Probability Score

Score 0.60870123685605

Ranking 278/25841 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 0.99814878870211

Ranking 1234/18225 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 0.93650262999599

Ranking 13217/18665 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 0.4766182216649

Ranking 688/20870 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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