GSTZ1
protein-codingglutathione S-transferase zeta 1, the group of Soluble glutathione S-transferases
Gene summary
This gene is a member of the glutathione S-transferase (GSTs) super-family which encodes multifunctional enzymes important in the detoxification of electrophilic molecules, including carcinogens, mutagens, and several therapeutic drugs, by conjugation with glutathione. This enzyme catalyzes the conversion of maleylacetoacetate to fumarylacetoacatate, which is one of the steps in the phenylalanine/tyrosine degradation pathway. Deficiency of a similar gene in mouse causes oxidative stress. Several transcript variants of this gene encode multiple protein isoforms. [provided by RefSeq, Jul 2015]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~10.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0060527
Submitter: ClinGen
*GSTZ1* was first reported in relation to autosomal recessive maleylacetoacetate isomerase deficiency in 2017 (Yang et al., 2017; PMID 27876694). The *GSTZ1* gene encodes an enzyme that is involved in the phenylalanine/phenylacetate degradation pathway. Most patients with the deficiency show only mild symptoms and remain well without treatment (Yang et al., 2017; PMID 27876694). Five variants (missense, nonsense, and intronic) that have been reported in seven probands in two publications (PMIDs: 27876694, 38535121) are included in this curation. This gene-disease association is also supported by biochemical assays and a mouse model (PMIDs: 12052898, 9417084). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally evaluated by the ClinGen Aminoacidopathy Gene Curation Expert Panel on March 22nd, 2019. It was reevaluated on September 9th, 2022, and on December 5th, 2024. As a result of this reevaluation, new genetic evidence was added (PMID: 38535121) but the classification did not change.
Clinical Genomic Database (CGD)
Manifestation: Biochemical
Intervention: General
Rationale: The clinical relevance of the condition is unclear
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GSTZ1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_145870.3. 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 | 2 | 1 | 3 | |||
| missense | 1 | 1 | 33 | 2 | 37 | |
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 2 | 1 | 3 | |||
| splice donor/acceptor (+/-2bp) | 2 | 1 | 3 | |||
| Total | 3 | 3 | 38 | 3 | 0 | 47 |
Highest pathogenic variant AF is 0.00072983385
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_665877.1 | 9 | MANE Select | |
| Ensembl | ENSP00000216465.5 | 9 | MANE Select | |
| RefSeq | NP_001299589.1 | 6 | Standard | |
| RefSeq | NP_001350632.1 | 9 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Tyrosine metabolism - Homo sapiens (human)
- Tyrosinemia, transient, of the newborn
- Dopamine beta-hydroxylase deficiency
- Disulfiram Action Pathway
- Phenylalanine and Tyrosine Metabolism
Biological Process
- L-phenylalanine catabolic process
- tyrosine catabolic process
- glutathione metabolic process
- regulation of acetyl-CoA biosynthetic process from pyruvate
- cellular oxidant detoxification
Molecular Function
- glutathione transferase activity
- glutathione peroxidase activity
- protein binding
- maleylacetoacetate isomerase activity
- hydrolase activity, acting on acid halide bonds, in C-halide compounds
Cellular Component
- mitochondrion
- mitochondrial matrix
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000216465
- Coding exons
- 9
- Length
- 10714
- Individuals with no LoFs
- 125696
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 52
- Defined
- 125748
- p
- 0.000207
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.0147 | 126 | 126 | 1.00 | 0.00000684 | 1391 |
| Missense (PolyPhen) | 28 | 35.312 | 0.79293 | 448 | ||
| Synonymous | -0.594 | 54 | 48.7 | 1.11 | 0.00000288 | 424 |
| Loss of Function | 0.0825 | 16 | 16.4 | 0.978 | 9.33e-7 | 165 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00031 | 0.00031 | rare |
| Latino/Admixed American | 0.00029 | 0.00029 | rare |
| Ashkenazi Jewish | 0.00032 | 0.00030 | rare |
| East Asian | 0.00022 | 0.00022 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00016 | 0.00016 | rare |
| South Asian | 0.00031 | 0.00029 | rare |
| Other | 0.00049 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Bifunctional enzyme showing minimal glutathione- conjugating activity with ethacrynic acid and 7-chloro-4- nitrobenz-2-oxa-1,3-diazole and maleylacetoacetate isomerase activity. Has also low glutathione peroxidase activity with T- butyl and cumene hydroperoxides. Is able to catalyze the glutathione dependent oxygenation of dichloroacetic acid to glyoxylic acid. {ECO:0000269|PubMed:10739172}.;
Recessive Scores
- pRec
- 0.305
Intolerance Scores
- LoFtool
- 0.929
- RVIS EVS
- 0.95
- RVIS percentile EVS
- 90.01
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.269
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | Medium | Medium | High |