PPM1D

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

Basic information

Region (hg38): 17:60600192-60666280

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

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 (10 variants)
• Intellectual developmental disorder with gastrointestinal difficulties and high pain threshold (8 variants)
• Inborn genetic diseases (4 variants)
• Familial cancer of breast (2 variants)
• Familial cancer of breast;Intellectual developmental disorder with gastrointestinal difficulties and high pain threshold (1 variants)
• Autosomal dominant non-syndromic intellectual disability (1 variants)
• Neurodevelopmental delay (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.

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.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	44	4	49
missense		1	65	20	5	91
nonsense	5	7	6			18
start loss						0
frameshift	15	20	17			52
inframe indel			1			1
splice donor/acceptor (+/-2bp)						0
splice region			1	2		3
non coding			2	7	13	22
Total	20	28	92	71	22

Highest pathogenic variant AF is 0.0000132

Variants in PPM1D

This is a list of pathogenic ClinVar variants found in the PPM1D region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
17-60600219-T-C			Benign (Jun 23, 2018)
17-60600423-G-C			Likely benign (Apr 06, 2023)
17-60600438-A-G			Likely benign (Nov 08, 2022)
17-60600465-G-A			Likely benign (Jun 09, 2023)
17-60600486-T-C			Likely benign (Oct 03, 2023)
17-60600492-A-C			Uncertain significance (Aug 16, 2022)
17-60600492-A-G			Likely benign (Aug 22, 2022)
17-60600495-C-G			Uncertain significance (May 01, 2023)
17-60600497-T-C			Uncertain significance (Sep 26, 2022)
17-60600504-G-A			Benign (Feb 01, 2024)
17-60600515-C-T			Uncertain significance (Feb 01, 2024)
17-60600526-A-C			Likely benign (Nov 27, 2023)
17-60600526-A-G			Uncertain significance (Oct 14, 2023)
17-60600542-G-A			Uncertain significance (Sep 22, 2022)
17-60600545-C-G		Intellectual developmental disorder with gastrointestinal difficulties and high pain threshold	Conflicting classifications of pathogenicity (Feb 01, 2024)
17-60600548-T-A			Uncertain significance (Mar 01, 2024)
17-60600548-T-C		Intellectual developmental disorder with gastrointestinal difficulties and high pain threshold	Uncertain significance (Apr 26, 2019)
17-60600551-C-G			Uncertain significance (Jan 08, 2024)
17-60600561-G-C		Inborn genetic diseases	Benign/Likely benign (Jan 25, 2024)
17-60600562-C-T			Uncertain significance (Aug 04, 2023)
17-60600574-T-G		Inborn genetic diseases	Uncertain significance (Aug 18, 2021)
17-60600581-C-G		Inborn genetic diseases	Likely benign (Feb 10, 2022)
17-60600586-C-G		Inborn genetic diseases	Uncertain significance (Sep 19, 2023)
17-60600586-C-T			Uncertain significance (Dec 05, 2022)
17-60600593-G-A		Inborn genetic diseases	Uncertain significance (Jan 29, 2024)

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