PSPH
protein-codingphosphoserine phosphatase, the group of HAD Asp-based non-protein phosphatases
Gene summary
The protein encoded by this gene belongs to a subfamily of the phosphotransferases. This encoded enzyme is responsible for the third and last step in L-serine formation. It catalyzes magnesium-dependent hydrolysis of L-phosphoserine and is also involved in an exchange reaction between L-serine and L-phosphoserine. Deficiency of this protein is thought to be linked to Williams syndrome. [provided by RefSeq, Jul 2008]
- PSP
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~40.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013531
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0013531
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013531
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0013531
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013531
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0009736
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0013531
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0018162
Submitter: ClinGen
*PSPH* was first reported in relation to autosomal recessive neurometabolic disorder due to serine deficiency in 2004 (Veiga-da-Cunha M, et al., PMID: 14673469; reported as phosphoserine phosphatase deficiency). At least 5 unique missense variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 4 probands in 4 publications (PMIDs: 26589312, 25080166, 14673469, 38816452). Variants in this gene segregated with disease in 5 additional family members. This gene-disease association is supported by the biochemical function of *PSPH* as a phosphoserine phosphatase and a knockout mouse model with prenatal lethality. Of note, this gene has been implicated in two neurometabolic disorders due to serine deficiency, phosphoserine phosphatase deficiency and Neu-Laxova syndrome. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no reported difference in molecular mechanisms or inheritance pattern and current assertions in the field suggest one broad phenotypic spectrum associated with serine biosynthesis defects encompassing both disorders (PMIDs: 28653176, 27161889, 26960553, 25152457). Therefore, all of the disease entities have been lumped into one disease entity, neurometabolic disorder due to serine deficiency. In summary, there is moderate evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This gene-disease pair was previously evaluated by the Aminoacidopathy GCEP on 09/29/2020. It was reevaluated on 10/14/2022 and again on 12/10/2024 when one new case was identified (PMID: 38816452). As a result of this reevaluation, the classification remained Moderate.
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Neurologic
Intervention: Biochemical
Rationale: Medical treatment (eg, with L-serine, glycine) has been reported as beneficial in terms of both biochemical parameters and clinical manifestations (head growth)
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PSPH variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_004577.4. 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 | 3 | 27 | 30 | |||
| missense | 2 | 65 | 9 | 76 | ||
| nonsense | 1 | 1 | 1 | 3 | ||
| start loss | 0 | |||||
| frameshift | 1 | 1 | 2 | |||
| splice donor/acceptor (+/-2bp) | 2 | 2 | ||||
| Total | 3 | 2 | 72 | 36 | 0 | 113 |
Highest pathogenic variant AF is 0.000006187387
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_004568.2 | 5 | MANE Select | |
| Ensembl | ENSP00000275605.3 | 5 | MANE Select | |
| RefSeq | NP_001357432.1 | 5 | Standard | |
| RefSeq | NP_001357433.1 | 5 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Glycine, serine and threonine metabolism - Homo sapiens (human)
- 3-Phosphoglycerate dehydrogenase deficiency
- Non Ketotic Hyperglycinemia
- Glycine and Serine Metabolism
- Dimethylglycine Dehydrogenase Deficiency
Biological Process
- L-serine metabolic process
- L-serine biosynthetic process
- response to mechanical stimulus
- dephosphorylation
- response to nutrient levels
Molecular Function
- magnesium ion binding
- phosphoserine phosphatase activity
- calcium ion binding
- phosphatase activity
- protein homodimerization activity
Cellular Component
- cytoplasm
- cytosol
- neuron projection
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000395471
- Coding exons
- 5
- Length
- 40554
- Individuals with no LoFs
- 125710
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 36
- Defined
- 125746
- p
- 0.000143
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.777 | 101 | 126 | 0.805 | 0.00000657 | 1451 |
| Missense (PolyPhen) | 32 | 48.594 | 0.65852 | 594 | ||
| Synonymous | 0.352 | 44 | 47.1 | 0.935 | 0.00000253 | 444 |
| Loss of Function | 1.16 | 6 | 9.96 | 0.602 | 5.87e-7 | 115 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00016 | 0.00016 | rare |
| Finnish | 0.0012 | 0.0012 | notable |
| European (Non-Finnish) | 0.000053 | 0.000053 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Catalyzes the last step in the biosynthesis of serine from carbohydrates. The reaction mechanism proceeds via the formation of a phosphoryl-enzyme intermediates. {ECO:0000269|PubMed:12777757}.;
- Disease
- DISEASE: Phosphoserine phosphatase deficiency (PSPHD) [MIM:614023]: An autosomal recessive disorder that results in pre- and postnatal growth retardation, moderate psychomotor retardation and facial features suggestive of Williams syndrome. {ECO:0000269|PubMed:14673469}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.282
- RVIS EVS
- 0.42
- RVIS percentile EVS
- 76.81
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.975
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |