PPP1R12A
protein-codingprotein phosphatase 1 regulatory subunit 12A, the group of Ankyrin repeat domain containing|Protein phosphatase 1 regulatory subunits|Myosin phosphatase targeting family
Gene summary
Myosin phosphatase target subunit 1, which is also called the myosin-binding subunit of myosin phosphatase, is one of the subunits of myosin phosphatase. Myosin phosphatase regulates the interaction of actin and myosin downstream of the guanosine triphosphatase Rho. The small guanosine triphosphatase Rho is implicated in myosin light chain (MLC) phosphorylation, which results in contraction of smooth muscle and interaction of actin and myosin in nonmuscle cells. The guanosine triphosphate (GTP)-bound, active form of RhoA (GTP.RhoA) specifically interacted with the myosin-binding subunit (MBS) of myosin phosphatase, which regulates the extent of phosphorylation of MLC. Rho-associated kinase (Rho-kinase), which is activated by GTP. RhoA, phosphorylated MBS and consequently inactivated myosin phosphatase. Overexpression of RhoA or activated RhoA in NIH 3T3 cells increased phosphorylation of MBS and MLC. Thus, Rho appears to inhibit myosin phosphatase through the action of Rho-kinase. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2009]
- MYPT1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~161.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0032934
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0032934
Submitter: ClinGen
The PPP1R12A gene is located on chromosome 12 at 12q21.2-q21.31 and encodes the protein phosphatase 1 regulatory subunit 12A protein. This protein forms part of myosin phosphatase, an enzyme that plays an important regulatory role in cell morphology and motility. PPP1R12A was first reported in relation to autosomal dominant genitourinary and/or brain malformation syndrome in 2020 (Hughes et al., 2020 PMID 31883643). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Twelve unique variants, all of which are predicted to result in protein truncation and nonsense mediated decay, have been reported in humans (Hughes et al., 2020 PMID 31883643). In the majority of cases, the variants were shown to have occurred de novo though parents weren’t available in a few cases. The mechanism for disease is predicted to be haploinsufficiency. This gene-disease relationship is supported by expression in the brain and urogenital system during embryonic development (Hughes et al., 2020 PMID 31883642) and data from C. elegans (Wissman et al., 1999 PMID 10208747), Drosophila (Tan et al., 2003 PMID 12505998), and zebrafish models (Weiser et al., 2009 PMID 19515695). In summary, there is strong evidence to support the relationship between PPP1R12A and autosomal dominant genitourinary and/or brain malformation syndrome. Additional reports in humans published at least three years from the first proposal of the association are needed to reach a definitive classification. This classification was approved by the ClinGen Syndromic Disorders Gene Curation Expert Panel on the meeting date 16Oct2020 (SOP Version 7).
Inheritance Pattern: AD
Disease ID:MONDO:0032934
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0032934
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0032934
Submitter: Illumina
The PPP1R12A gene is located on chromosome 12 at 12q21.2-q21.31 and encodes protein phosphatase 1 regulatory subunit 12A. This protein forms part of myosin phosphatase, an enzyme that plays an important regulatory role in cell morphology and motility. PPP1R12A was first reported in relation to autosomal dominant genitourinary and/or brain malformation syndrome in 2020 (31883643: Hughes et al. 2020). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Twelve unique variants, all of which were predicted null, have been reported in humans (31883643: Hughes et al. 2020). In the majority of cases, the variants were shown to have occurred de novo. The mechanism for disease is haploinsufficiency. This gene-disease relationship is supported by expression in the brain and urogenital system during embryonic development (31883643: Hughes et al. 2020) and overlapping phenotypes observed in C. elegans (10208747: Wissman et al. 1999), Drosophila (12505998: Tan et al. 2003), and zebrafish models (19515695: Weiser et al. 2009). In summary, there is strong evidence to support the relationship between PPP1R12A and autosomal dominant genitourinary and/or brain malformation syndrome. Additional reports in humans published at least three years from the first proposal of the association are needed to reach a definitive classification.
Inheritance Pattern: AD
Disease ID:MONDO:0032934
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Genitourinary; Gastrointestinal; Neurologic
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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PPP1R12A variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002480.3. 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 | 5 | 27 | 6 | 38 | ||
| missense | 4 | 154 | 32 | 6 | 196 | |
| nonsense | 5 | 6 | 1 | 12 | ||
| start loss | 1 | 1 | ||||
| frameshift | 10 | 12 | 3 | 25 | ||
| splice donor/acceptor (+/-2bp) | 3 | 6 | 6 | 1 | 16 | |
| Total | 18 | 28 | 170 | 60 | 12 | 288 |
Highest pathogenic variant AF is 0.00015245924
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002471.1 | 25 | MANE Select | |
| Ensembl | ENSP00000389168.2 | 25 | MANE Select | |
| RefSeq | NP_001137357.1 | 25 | Standard | |
| RefSeq | NP_001137358.1 | 24 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| ppp1r12a | Danio rerio | Structure: neuroepithelial cell Quality: decreased accumulation abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Platelet activation - Homo sapiens (human)
- Focal adhesion - Homo sapiens (human)
- Oxytocin signaling pathway - Homo sapiens (human)
- Regulation of actin cytoskeleton - Homo sapiens (human)
- cAMP signaling pathway - Homo sapiens (human)
Biological Process
- mitotic cell cycle
- protein dephosphorylation
- centrosome cycle
- signal transduction
- regulation of cell adhesion
Molecular Function
- enzyme inhibitor activity
- protein binding
- phosphatase regulator activity
- protein kinase binding
- 14-3-3 protein binding
Cellular Component
- kinetochore
- nucleoplasm
- cytoplasm
- centrosome
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000450142
- Coding exons
- 25
- Length
- 161898
- Individuals with no LoFs
- 124534
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 28
- Defined
- 124562
- p
- 0.000112
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.64 | 342 | 509 | 0.671 | 0.0000254 | 6674 |
| Missense (PolyPhen) | 133 | 259.93 | 0.51167 | 3302 | ||
| Synonymous | 0.186 | 173 | 176 | 0.982 | 0.00000841 | 1942 |
| Loss of Function | 6.81 | 3 | 59.8 | 0.0501 | 0.00000338 | 772 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00013 | 0.00013 | rare |
| Latino/Admixed American | 0.000069 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00021 | 0.00021 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Key regulator of protein phosphatase 1C (PPP1C). Mediates binding to myosin. As part of the PPP1C complex, involved in dephosphorylation of PLK1. Capable of inhibiting HIF1AN- dependent suppression of HIF1A activity. {ECO:0000269|PubMed:18477460, ECO:0000269|PubMed:19245366, ECO:0000269|PubMed:20354225}.;
Recessive Scores
- pRec
- 0.418
Intolerance Scores
- RVIS EVS
- -0.86
- RVIS percentile EVS
- 10.85
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- H
- Indispensability pred.
- N
- Indispensability score
- 0.329
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |