PPM1D

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

Basic information

Region (hg38): 17:60600193-60666280

Links

ENSG00000170836

∙ NCBI:8493 ∙ OMIM:605100 ∙ HGNC:9277 ∙ Uniprot:O15297 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

hereditary breast carcinoma (No Known Disease Relationship), mode of inheritance: Unknown
hereditary breast carcinoma (Disputed Evidence), mode of inheritance: AD
intellectual developmental disorder with gastrointestinal difficulties and high pain threshold (Moderate), mode of inheritance: AD
intellectual developmental disorder with gastrointestinal difficulties and high pain threshold (Strong), mode of inheritance: AD
syndromic intellectual disability (Definitive), mode of inheritance: AD
intellectual developmental disorder with gastrointestinal difficulties and high pain threshold (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Intellectual developmental disorder with gastrointestinal difficulties and high pain threhold (Jansen-De Vries syndrome)	AD	General	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	Craniofacial; Gastrointestinal; Musculoskeletal; Neurologic; Ophthalmologic	28343630

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PPM1D gene.

not_provided (264 variants)
Inborn_genetic_diseases (51 variants)
Intellectual_developmental_disorder_with_gastrointestinal_difficulties_and_high_pain_threshold (51 variants)
Hereditary_cancer-predisposing_syndrome (16 variants)
Familial_cancer_of_breast (13 variants)
not_specified (10 variants)
PPM1D-related_disorder (9 variants)
Autosomal_dominant_non-syndromic_intellectual_disability (1 variants)
Ovarian_cancer (1 variants)
Neurodevelopmental_delay (1 variants)
Lung_carcinoma (1 variants)
See_cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PPM1D gene is commonly pathogenic or not. These statistics are base on transcript: NM_000003620.4. Only rare variants are included in the table.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUSVUS	Likely benignLB	BenignB	Sum
synonymous				62 clinvar	3 clinvar	65
missense	1 clinvar	1 clinvar	106 clinvar	37 clinvar	6 clinvar	151
nonsense	8 clinvar	9 clinvar	11 clinvar			28
start loss						0
frameshift	22 clinvar	28 clinvar	27 clinvar			77
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	31	38	145	99	9

Highest pathogenic variant AF is 0.0000192067

Loading clinvar variants...

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PPM1D	protein_coding	protein_coding	ENST00000305921	6	64306

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.23e-11	0.415	125706	0	42	125748	0.000167

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.70	200	340	0.588	0.0000170	3920
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000116	0.000116
Ashkenazi Jewish	0.0000993	0.0000992
East Asian	0.0000544	0.0000544
Finnish	0.000143	0.000139
European (Non-Finnish)	0.000265	0.000264
Middle Eastern	0.0000544	0.0000544
South Asian	0.0000981	0.0000980
Other	0.00	0.00

dbNSFP

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.;
Pathway: p53 signaling pathway - Homo sapiens (human);ATM Signaling Network in Development and Disease;Transcriptional regulation by RUNX2;Gene expression (Transcription);Generic Transcription Pathway;RNA Polymerase II Transcription;p53 pathway (Consensus)

Recessive Scores

pRec: 0.273

Intolerance Scores

loftool: 0.835
rvis_EVS: -0.34
rvis_percentile_EVS: 30.37

Haploinsufficiency Scores

pHI: 0.619
hipred: Y
hipred_score: 0.663
ghis: 0.593

Essentials

essential_gene_CRISPR: N
essential_gene_CRISPR2: E
essential_gene_gene_trap: N
gene_indispensability_pred: E
gene_indispensability_score: 0.907

Gene Damage Prediction

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

Mouse Genome Informatics

Gene name: Ppm1d
Phenotype: immune system phenotype; neoplasm; hematopoietic system phenotype; reproductive system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); homeostasis/metabolism phenotype; cellular phenotype; endocrine/exocrine gland phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan);

Gene ontology

Biological process: G2/M transition of mitotic cell cycle;DNA methylation;chromatin silencing;transcription initiation from RNA polymerase II promoter;protein phosphorylation;protein dephosphorylation;negative regulation of cell population proliferation;cellular response to starvation;response to radiation;response to bacterium;DNA damage response, signal transduction by p53 class mediator;peptidyl-threonine dephosphorylation;negative regulation of gene expression, epigenetic
Cellular component: nucleus;nucleoplasm;cytosol
Molecular function: protein serine/threonine kinase activity;protein serine/threonine phosphatase activity;magnesium-dependent protein serine/threonine phosphatase activity;protein binding;metal ion binding;mitogen-activated protein kinase binding