Human Gene Module / Chromosome 17 / PPM1D

PPM1Dprotein phosphatase, Mg2+/Mn2+ dependent 1D

SFARI Gene Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
4 / 11
Rare Variants / Common Variants
56 / 0
Aliases
PPM1D, PP2C-DELTA,  WIP1
Associated Syndromes
Jansen-de Vries syndrome, DD, Pediatric Acute-Onset Neuropsychiatric Syndrome (P, Jansen-de Vries syndrome, DD, ID
Chromosome Band
17q23.2
Associated Disorders
DD/NDD, ASD
Relevance to Autism

A de novo nonsense variant in the PPM1D gene was identifed in an ASD proband from the Simons Simplex Collection in Sanders et al., 2012. Detailed phenotypic characterization of this proband, along with 13 other individuals with truncating variants in the last 2 exons of the PPM1D gene, in Jansen et al., 2017 identified an intellectual disability syndrome; behavioral problems were observed in 11/14 individuals, with ASD reported in 4/14 individuals in this report.

Molecular Function

The protein encoded by this gene is a member of the PP2C family of Ser/Thr protein phosphatases. PP2C family members are known to be negative regulators of cell stress response pathways. The expression of this gene is induced in a p53-dependent manner in response to various environmental stresses. While being induced by tumor suppressor protein TP53/p53, this phosphatase negatively regulates the activity of p38 MAP kinase, MAPK/p38, through which it reduces the phosphorylation of p53, and in turn suppresses p53-mediated transcription and apoptosis. This phosphatase thus mediates a feedback regulation of p38-p53 signaling that contributes to growth inhibition and the suppression of stress induced apoptosis.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PPM1D (11 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary De novo mutations revealed by whole-exome sequencing are strongly associated with autism Sanders SJ , et al. (2012) Yes -
2 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
3 Recent Recommendation De Novo Truncating Mutations in the Last and Penultimate Exons of PPM1D Cause an Intellectual Disability Syndrome Jansen S , et al. (2017) No ASD
4 Support A Statistical Framework for Mapping Risk Genes from De Novo Mutations in Whole-Genome-Sequencing Studies Liu Y , et al. (2018) Yes -
5 Support Novel truncating PPM1D mutation in a patient with intellectual disability Porrmann J , et al. (2018) No -
6 Support Two unrelated girls with intellectual disability associated with a truncating mutation in the PPM1D penultimate exon Kuroda Y , et al. (2019) No DD
7 Support - Mahjani B et al. (2021) Yes -
8 Support - Tsai MM et al. (2022) No ID
9 Support - Trifiletti R et al. (2022) No DD
10 Recent Recommendation - Wojcik MH et al. (2023) No ADHD, autistic features
11 Support - Axel Schmidt et al. (2024) No -
Rare Variants   (56)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - loss_of_function_variant De novo - - 29754769 Liu Y , et al. (2018)
- - regulatory_region_variant De novo - - 29754769 Liu Y , et al. (2018)
c.1210C>T p.Gln404Ter stop_gained De novo - - 28343630 Jansen S , et al. (2017)
c.1654C>T p.Arg552Ter stop_gained Unknown - - 28343630 Jansen S , et al. (2017)
c.1210C>T p.Gln404Ter stop_gained De novo - - 37183572 Wojcik MH et al. (2023)
c.1262C>A p.Ser421Ter stop_gained De novo - - 37183572 Wojcik MH et al. (2023)
c.1270G>T p.Glu424Ter stop_gained De novo - - 37183572 Wojcik MH et al. (2023)
c.1280G>A p.Trp427Ter stop_gained De novo - - 37183572 Wojcik MH et al. (2023)
c.1281G>A p.Trp427Ter stop_gained De novo - - 37183572 Wojcik MH et al. (2023)
c.1349T>G p.Leu450Ter stop_gained De novo - - 37183572 Wojcik MH et al. (2023)
c.1451T>G p.Leu484Ter stop_gained De novo - - 37183572 Wojcik MH et al. (2023)
c.1547C>G p.Ser516Ter stop_gained De novo - - 37183572 Wojcik MH et al. (2023)
c.1573G>T p.Glu525Ter stop_gained De novo - - 37183572 Wojcik MH et al. (2023)
c.1654C>T p.Arg552Ter stop_gained De novo - - 37183572 Wojcik MH et al. (2023)
c.1547C>G p.Ser516Ter stop_gained De novo - - 35773312 Trifiletti R et al. (2022)
c.1444del p.Leu482Ter frameshift_variant De novo - - 37183572 Wojcik MH et al. (2023)
c.1221T>A p.Cys407Ter stop_gained De novo - Simplex 28343630 Jansen S , et al. (2017)
c.1281G>A p.Trp427Ter stop_gained De novo - Simplex 28343630 Jansen S , et al. (2017)
c.1339G>T p.Glu447Ter stop_gained De novo - Simplex 28343630 Jansen S , et al. (2017)
c.1525G>C p.Asp509His missense_variant Unknown - - 25363760 De Rubeis S , et al. (2014)
c.1262C>A p.Ser421Ter stop_gained Familial Maternal - 37183572 Wojcik MH et al. (2023)
c.1573G>T p.Glu525Ter stop_gained Familial Maternal - 37183572 Wojcik MH et al. (2023)
c.1281G>A p.Trp427Ter stop_gained De novo - Simplex 22495306 Sanders SJ , et al. (2012)
c.1260+137del - frameshift_variant De novo - Simplex 29758292 Porrmann J , et al. (2018)
c.1277dup p.Trp427MetfsTer7 frameshift_variant De novo - - 35016835 Tsai MM et al. (2022)
c.1270dup p.Glu424GlyfsTer10 frameshift_variant De novo - - 35016835 Tsai MM et al. (2022)
c.1057C>T p.Arg353Ter stop_gained Familial Maternal - 25363760 De Rubeis S , et al. (2014)
c.1057C>T p.Arg353Ter stop_gained Familial Paternal - 25363760 De Rubeis S , et al. (2014)
c.1200del p.Tyr401IlefsTer8 frameshift_variant De novo - - 37183572 Wojcik MH et al. (2023)
c.1212del p.Glu405LysfsTer4 frameshift_variant Unknown - - 37183572 Wojcik MH et al. (2023)
c.1278dup p.Trp427MetfsTer7 frameshift_variant De novo - - 37183572 Wojcik MH et al. (2023)
c.1535del p.Asn512IlefsTer2 frameshift_variant De novo - - 37183572 Wojcik MH et al. (2023)
c.1045dup p.Met349AsnfsTer19 frameshift_variant De novo - - 28343630 Jansen S , et al. (2017)
c.1259dup p.Ser421ValfsTer13 frameshift_variant De novo - - 37183572 Wojcik MH et al. (2023)
c.1033dup p.Ser345PhefsTer23 splice_site_variant De novo - - 28343630 Jansen S , et al. (2017)
c.131C>G p.Ser44Trp missense_variant Familial - Multiplex 35773312 Trifiletti R et al. (2022)
c.1091G>A p.Arg364Gln missense_variant Familial Paternal - 25363760 De Rubeis S , et al. (2014)
c.1525G>C p.Asp509His missense_variant Familial Maternal - 25363760 De Rubeis S , et al. (2014)
c.1041_1042dup p.Lys348ThrfsTer5 frameshift_variant De novo - - 28343630 Jansen S , et al. (2017)
c.1269_1270del p.Glu424GlyfsTer9 frameshift_variant De novo - - 37183572 Wojcik MH et al. (2023)
c.1272_1273dup p.Asp425GlyfsTer7 frameshift_variant De novo - - 37183572 Wojcik MH et al. (2023)
c.1565_1566dup p.Ala523LysfsTer17 frameshift_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.1204_1208del p.Asn402SerfsTer30 frameshift_variant De novo - - 37183572 Wojcik MH et al. (2023)
c.1225_1226del p.Met409AspfsTer24 frameshift_variant De novo - - 37183572 Wojcik MH et al. (2023)
c.988del p.Gln330ArgfsTer9 frameshift_variant De novo - Simplex 28343630 Jansen S , et al. (2017)
c.1387_1388insTA p.Gly463ValfsTer3 frameshift_variant De novo - - 37183572 Wojcik MH et al. (2023)
c.1022dup p.His342AlafsTer26 frameshift_variant De novo - Simplex 28343630 Jansen S , et al. (2017)
c.1045dup p.Met349AsnfsTer19 frameshift_variant De novo - Simplex 28343630 Jansen S , et al. (2017)
c.1606del p.Arg536GlyfsTer3 frameshift_variant Familial Maternal - 37183572 Wojcik MH et al. (2023)
c.1565_1566dup p.Ala523LysfsTer17 frameshift_variant Unknown - - 25363760 De Rubeis S , et al. (2014)
c.1237_1238del p.Pro413MetfsTer20 frameshift_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.960_963del p.Pro321HisfsTer17 frameshift_variant De novo - Simplex 28343630 Jansen S , et al. (2017)
c.1176_1183del p.Leu393AspfsTer2 frameshift_variant De novo - Simplex 28343630 Jansen S , et al. (2017)
c.1188_1191del p.Asp397AlafsTer11 frameshift_variant Familial Paternal - 37183572 Wojcik MH et al. (2023)
c.1022_1023insACCA p.His342ProfsTer27 frameshift_variant De novo - Simplex 30795918 Kuroda Y , et al. (2019)
c.1028_1029insCAAG p.Gln344LysfsTer25 frameshift_variant De novo - Simplex 30795918 Kuroda Y , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

A de novo nonsense variant in the PPM1D gene was identifed in an ASD proband from the Simons Simplex Collection in Sanders et al., 2012. Detailed phenotypic characterization of this proband, along with 13 other individuals with truncating variants in the last 2 exons of the PPM1D gene, in Jansen et al., 2017 identified an intellectual disability syndrome; behavioral problems were observed in 11/14 individuals, with ASD reported in 4/14 individuals in this report. TADA-Annotations (TADA-A) analysis of whole-genome sequencing data from five studies with a total of 314 ASD-affected subjects in Liu et al., 2018 identified PPM1D as an ASD risk gene with a false discovery rate (FDR) < 0.3; among the de novo variants associated with this gene in ASD subjects was a loss-of-function variant and a conserved regulatory SNV.

Score Delta: Score remained at 2S

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.

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
3S
icon
2S

Decreased from 3S to 2S

Description

A de novo nonsense variant in the PPM1D gene was identifed in an ASD proband from the Simons Simplex Collection in Sanders et al., 2012. Detailed phenotypic characterization of this proband, along with 13 other individuals with truncating variants in the last 2 exons of the PPM1D gene, in Jansen et al., 2017 identified an intellectual disability syndrome; behavioral problems were observed in 11/14 individuals, with ASD reported in 4/14 individuals in this report. TADA-Annotations (TADA-A) analysis of whole-genome sequencing data from five studies with a total of 314 ASD-affected subjects in Liu et al., 2018 identified PPM1D as an ASD risk gene with a false discovery rate (FDR) < 0.3; among the de novo variants associated with this gene in ASD subjects was a loss-of-function variant and a conserved regulatory SNV.

10/1/2019
4S
icon
3S

Decreased from 4S to 3S

New Scoring Scheme
Description

A de novo nonsense variant in the PPM1D gene was identifed in an ASD proband from the Simons Simplex Collection in Sanders et al., 2012. Detailed phenotypic characterization of this proband, along with 13 other individuals with truncating variants in the last 2 exons of the PPM1D gene, in Jansen et al., 2017 identified an intellectual disability syndrome; behavioral problems were observed in 11/14 individuals, with ASD reported in 4/14 individuals in this report. TADA-Annotations (TADA-A) analysis of whole-genome sequencing data from five studies with a total of 314 ASD-affected subjects in Liu et al., 2018 identified PPM1D as an ASD risk gene with a false discovery rate (FDR) < 0.3; among the de novo variants associated with this gene in ASD subjects was a loss-of-function variant and a conserved regulatory SNV.

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

Decreased from 4S to 4S

Description

A de novo nonsense variant in the PPM1D gene was identifed in an ASD proband from the Simons Simplex Collection in Sanders et al., 2012. Detailed phenotypic characterization of this proband, along with 13 other individuals with truncating variants in the last 2 exons of the PPM1D gene, in Jansen et al., 2017 identified an intellectual disability syndrome; behavioral problems were observed in 11/14 individuals, with ASD reported in 4/14 individuals in this report. TADA-Annotations (TADA-A) analysis of whole-genome sequencing data from five studies with a total of 314 ASD-affected subjects in Liu et al., 2018 identified PPM1D as an ASD risk gene with a false discovery rate (FDR) < 0.3; among the de novo variants associated with this gene in ASD subjects was a loss-of-function variant and a conserved regulatory SNV.

Reports Added
[Two unrelated girls with intellectual disability associated with a truncating mutation in the PPM1D penultimate exon.2019]
7/1/2018
S
icon
4S

Increased from S to 4S

Description

A de novo nonsense variant in the PPM1D gene was identifed in an ASD proband from the Simons Simplex Collection in Sanders et al., 2012. Detailed phenotypic characterization of this proband, along with 13 other individuals with truncating variants in the last 2 exons of the PPM1D gene, in Jansen et al., 2017 identified an intellectual disability syndrome; behavioral problems were observed in 11/14 individuals, with ASD reported in 4/14 individuals in this report. TADA-Annotations (TADA-A) analysis of whole-genome sequencing data from five studies with a total of 314 ASD-affected subjects in Liu et al., 2018 identified PPM1D as an ASD risk gene with a false discovery rate (FDR) < 0.3; among the de novo variants associated with this gene in ASD subjects was a loss-of-function variant and a conserved regulatory SNV.

Krishnan Probability Score

Score 0.49962235712824

Ranking 2145/25841 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 0.0011680041961181

Ranking 11676/18225 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 0.19971190775849

Ranking 111/18665 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 0.47475345564565

Ranking 706/20870 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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