PPM1D

protein-coding

protein phosphatase, Mg2+/Mn2+ dependent 1D, the group of Protein phosphatases, Mg2+/Mn2+ dependent

Gene summary

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. This gene is located in a chromosomal region known to be amplified in breast cancer. The amplification of this gene has been detected in both breast cancer cell line and primary breast tumors, which suggests a role of this gene in cancer development. [provided by RefSeq, Jul 2008]

MANE transcript

NM_003620.4

Inheritance

ClinVar variants

P:89U:168B:127

Top phenotype

Intellectual developmental disorder with gastrointestinal difficulties and high pain threhold (Jansen-De Vries syndrome)

gnomAD constraint

pLI —, LoF o/e 0.75

Max pathogenic AF

—

Genomic locus

chr17:60,600,193-60,666,280

External References & Databases

Ensembl (ENSG00000170836)

Transcript & Mutation Effects

hg38 • Region Span ~66.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary breast carcinomaNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0016419

Submitter: Ambry Genetics

intellectual developmental disorder with gastrointestinal difficulties and high pain thresholdSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0044318

Submitter: PanelApp Australia

syndromic intellectual disabilityDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000508

Submitter: ClinGen

The *PPM1D* gene encodes a member of the PP2C family of serine/threonine protein phosphatases which are negative regulators of cell stress response pathways. Association between *PPM1D* variants and autosomal dominant syndromic intellectual disability (Jansen-de Vries syndrome) was first reported in 2017 (Jansen et al., PMID: 28343630). Since then, at least 20 truncating variants, most of which are *de novo*, have been reported in individuals with intellectual disability and/or developmental delay, hypotonia, behavioral problems including autism spectrum disorder, high pain threshold, and facial dysmorphism (PMIDs: 28343630, 29758292, 30795918, 30979967, 31916397, 32399599). All the variants are located in the last or penultimate exon and are expected to escape nonsense-mediated mRNA decay, which is supported by the presence of truncated *PPM1D* transcripts in patient-derived cells (PMID: 28343630). In addition, these cells showed a cell-growth disadvantage after exposure to ionizing radiation, suggesting a possible effect on the stress-response pathway (PMID: 28343630). *PPM1D* has a pLI of 0 in gnomAD (v2.1.1), with 49 observed truncating variants. Mosaic C-terminal truncating *PPM1D* variants in blood are associated with clonal hematopoiesis during aging and cancer therapy (PMID: 34963005). This suggests that some of the truncating variants in gnomAD, many of which exhibit allelic imbalance, may represent somatic mosaicism. In summary, *PPM1D* is definitively associated with autosomal dominant syndromic intellectual disability. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on February 15, 2022 (SOP Version 8).

hereditary breast carcinomaNO_KNOWN

Inheritance Pattern: Unknown

Disease ID:MONDO:0016419

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder with gastrointestinal difficulties and high pain thresholdMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0044318

Submitter: Ambry Genetics

intellectual developmental disorder with gastrointestinal difficulties and high pain thresholdSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0044318

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder with gastrointestinal difficulties and high pain thresholdDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0044318

Submitter: G2P

Clinical Genomic Database (CGD)

Intellectual developmental disorder with gastrointestinal difficulties and high pain threhold (Jansen-De Vries syndrome)AD

Manifestation: Craniofacial; Gastrointestinal; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 28343630

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PPM1D variants in ClinVar

12 Conditions Cataloged

not providedTotal: 305

Inborn genetic diseasesTotal: 66

Intellectual developmental disorder with gastrointestinal difficulties and high pain thresholdTotal: 66

not specifiedTotal: 38

PPM1D-related disorderTotal: 20

Hereditary cancer-predisposing syndromeTotal: 16

Familial cancer of breastTotal: 14

Autosomal dominant non-syndromic intellectual disabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003620.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	73 clinvar	3 clinvar	77
missense		1 clinvar	126 clinvar	46 clinvar	5 clinvar	178
nonsense	8 clinvar	14 clinvar	9 clinvar			31
start loss						0
frameshift	24 clinvar	41 clinvar	28 clinvar			93
splice donor/acceptor (+/-2bp)		1 clinvar	4 clinvar			5
Total	32	57	168	119	8	384

Highest pathogenic variant AF is 0.00001920675

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 19 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003620.4	RefSeq	NP_003611.1	6	MANE Select
ENST00000305921.8	Ensembl	ENSP00000306682.2	6	MANE Select
ENST00000392995.7	Ensembl	ENSP00000376720.3	6	Standard
ENST00000629650.3	Ensembl	ENSP00000486573.2	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

p53 signaling pathway - Homo sapiens (human)
ATM Signaling Network in Development and Disease
Transcriptional regulation by RUNX2
Gene expression (Transcription)
Generic Transcription Pathway

Biological Process

G2/M transition of mitotic cell cycle
DNA methylation
chromatin silencing
transcription initiation from RNA polymerase II promoter
protein phosphorylation

Molecular Function

protein serine/threonine kinase activity
protein serine/threonine phosphatase activity
magnesium-dependent protein serine/threonine phosphatase activity
protein binding
metal ion binding

Cellular Component

nucleus
nucleoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000305921
Coding exons: 6
Length: 64306
Individuals with no LoFs: 125706
Homozygous LoFs: 0
Heterozygous LoFs: 42
Defined: 125748
p: 0.000167

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.70	200	340	0.588	0.0000170	3920
Missense (PolyPhen)		37	126.13	0.29334		1383
Synonymous	1.22	104	121	0.859	0.00000576	1221
Loss of Function	1.17	20	26.5	0.754	0.00000168	265

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00027	0.00026	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the negative regulation of p53 expression (PubMed:23242139). Required for the relief of p53-dependent checkpoint mediated cell cycle arrest. Binds to and dephosphorylates 'Ser-15' of TP53 and 'Ser-345' of CHEK1 which contributes to the functional inactivation of these proteins (PubMed:15870257, PubMed:16311512). Mediates MAPK14 dephosphorylation and inactivation (PubMed:21283629). Is also an important regulator of global heterochromatin silencing and critical in maintaining genome integrity (By similarity). {ECO:0000250|UniProtKB:Q9QZ67, ECO:0000269|PubMed:15870257, ECO:0000269|PubMed:16311512, ECO:0000269|PubMed:21283629, ECO:0000269|PubMed:23242139}.;
Disease: DISEASE: Intellectual developmental disorder with gastrointestinal difficulties and high pain threshold (IDDGIP) [MIM:617450]: An autosomal dominant neurodevelopmental disorder characterized by mild to severe intellectual disability, psychomotor developmental delay, speech delay, and behavioral manifestations including attention deficit-hyperactivity disorder, autism and anxiety disorders. Most patients have variable additional features, including feeding and gastrointestinal difficulties, high pain threshold, hypersensitivity to sound, hypotonia, broad-based gait, and dysmorphic features, including mild facial abnormalities, strabismus, and small hands and feet. {ECO:0000269|PubMed:28343630}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Breast cancer (BC) [MIM:114480]: A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. {ECO:0000269|PubMed:23242139}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry.; DISEASE: Ovarian cancer (OC) [MIM:167000]: The term ovarian cancer defines malignancies originating from ovarian tissue. Although many histologic types of ovarian tumors have been described, epithelial ovarian carcinoma is the most common form. Ovarian cancers are often asymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients are diagnosed with advanced disease. {ECO:0000269|PubMed:23242139}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.273

Intolerance Scores

LoFtool: 0.835
RVIS EVS: -0.34
RVIS percentile EVS: 30.37

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.907

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium