GPX4

glutathione peroxidase 4, the group of Selenoproteins

Basic information

Region (hg38): 19:1103981-1106791

Links

ENSG00000167468 ∙ NCBI:2879 ∙ OMIM:138322 ∙ HGNC:4556 ∙ Uniprot:P36969 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• spondylometaphyseal dysplasia, Sedaghatian type (Strong), mode of inheritance: AR
• spondylometaphyseal dysplasia, Sedaghatian type (Moderate), mode of inheritance: AR
• spondylometaphyseal dysplasia, Sedaghatian type (Supportive), mode of inheritance: AR
• spondylometaphyseal dysplasia, Sedaghatian type (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Sedaghatian-type spondylometaphyseal dysplasia	AR	Cardiovascular	The condition can involve congenital cardiac anomalies (including structural anomalies and arrhythmia), and awareness may allow early management	Cardiovascular; Musculoskeletal; Neurologic	22529034; 24706940

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GPX4 gene.

• not provided (115 variants)
• Inborn genetic diseases (18 variants)
• Spondylometaphyseal dysplasia, Sedaghatian type (6 variants)
• GPX4-related condition (2 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GPX4 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				15	3	18
missense			39	1	1	41
nonsense						0
start loss						0
frameshift	1	3				4
inframe indel						0
splice donor/acceptor (+/-2bp)		1	1			2
splice region			4	5	1	10
non coding	2		15	21	14	52
Total	3	4	55	37	18

Highest pathogenic variant AF is 0.0000198

Variants in GPX4

This is a list of pathogenic ClinVar variants found in the GPX4 region.

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

Position	Type	Phenotype	Significance	ClinVar
19-1104038-G-A		GPX4-related disorder	Likely benign (Jul 22, 2019)
19-1104053-G-T		Inborn genetic diseases	Uncertain significance (Dec 19, 2022)
19-1104079-G-A		GPX4-related disorder	Benign (Oct 28, 2019)
19-1104104-G-A		Inborn genetic diseases	Uncertain significance (Nov 03, 2022)
19-1104116-G-C		Inborn genetic diseases	Uncertain significance (Oct 25, 2022)
19-1104439-G-C			Benign (May 12, 2021)
19-1104528-C-G			Benign (May 21, 2021)
19-1104564-G-T			Benign (May 12, 2021)
19-1104746-G-T			Likely benign (Nov 27, 2023)
19-1104753-G-A		Inborn genetic diseases	Uncertain significance (Jan 03, 2024)
19-1104757-C-T			Uncertain significance (Mar 18, 2022)
19-1104759-C-T		Inborn genetic diseases	Uncertain significance (Jul 07, 2023)
19-1104760-C-T			Uncertain significance (Mar 18, 2021)
19-1104761-C-T			Likely benign (Nov 10, 2023)
19-1104766-G-A		Inborn genetic diseases	Uncertain significance (Nov 03, 2023)
19-1104778-G-C		Inborn genetic diseases	Uncertain significance (Dec 16, 2022)
19-1104783-C-T			Pathogenic (Aug 23, 2022)
19-1104785-G-T			Uncertain significance (Jul 26, 2022)
19-1104836-G-A			Likely benign (Oct 22, 2023)
19-1104839-C-CA			Pathogenic (Jul 05, 2022)
19-1104844-G-C		Inborn genetic diseases	Uncertain significance (Jan 23, 2024)
19-1104845-C-A			Likely benign (Nov 21, 2023)
19-1104853-C-A			Uncertain significance (Jan 19, 2024)
19-1104862-G-A			Uncertain significance (Aug 17, 2023)
19-1104865-G-A		Spondylometaphyseal dysplasia, Sedaghatian type	Conflicting classifications of pathogenicity (Sep 30, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GPX4	protein_coding	protein_coding	ENST00000354171	7	2852

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0000479	0.673	124695	0	29	124724	0.000116

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-1.08	159	125	1.27	0.00000753	1285
Missense in Polyphen		41	47.342	0.86604		495
Synonymous	-3.47	89	55.9	1.59	0.00000435	359
Loss of Function	0.906	8	11.3	0.709	5.33e-7	125

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000320	0.000316
Ashkenazi Jewish	0.00	0.00
East Asian	0.000784	0.000668
Finnish	0.0000930	0.0000928
European (Non-Finnish)	0.0000632	0.0000619
Middle Eastern	0.000784	0.000668
South Asian	0.0000654	0.0000654
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Essential antioxidant peroxidase that directly reduces phospholipid hydroperoxide even if they are incorporated in membranes and lipoproteins (By similarity). Can also reduce fatty acid hydroperoxide, cholesterol hydroperoxide and thymine hydroperoxide (By similarity). Plays a key role in protecting cells from oxidative damage by preventing membrane lipid peroxidation (By similarity). Required to prevent cells from ferroptosis, a non-apoptotic cell death resulting from an iron- dependent accumulation of lipid reactive oxygen species (PubMed:24439385). The presence of selenocysteine (Sec) versus Cys at the active site is essential for life: it provides resistance to overoxidation and prevents cells against ferroptosis (By similarity). The presence of Sec at the active site is also essential for the survival of a specific type of parvalbumin- positive interneurons, thereby preventing against fatal epileptic seizures (By similarity). May be required to protect cells from the toxicity of ingested lipid hydroperoxides (By similarity). Required for normal sperm development and male fertility (By similarity). Essential for maturation and survival of photoreceptor cells (By similarity). Plays a role in a primary T- cell response to viral and parasitic infection by protecting T- cells from ferroptosis and by supporting T-cell expansion (By similarity). {ECO:0000250|UniProtKB:O70325, ECO:0000250|UniProtKB:P36968, ECO:0000269|PubMed:24439385}.
• Pathway: Glutathione metabolism - Homo sapiens (human);Ferroptosis - Homo sapiens (human);Glutathione metabolism;Selenium Micronutrient Network;Folate Metabolism;Selenium Metabolism and Selenoproteins;One carbon metabolism and related pathways;Metapathway biotransformation Phase I and II;glutathione redox reactions I;Metabolism of lipids;Synthesis of 5-eicosatetraenoic acids;Synthesis of 15-eicosatetraenoic acid derivatives;Synthesis of 12-eicosatetraenoic acid derivatives;Arachidonic acid metabolism;Metabolism;Biosynthesis of E-series 18(S)-resolvins;Biosynthesis of E-series 18(R)-resolvins;Biosynthesis of EPA-derived SPMs;Biosynthesis of D-series resolvins;Biosynthesis of aspirin-triggered D-series resolvins;Biosynthesis of DHA-derived SPMs;Biosynthesis of specialized proresolving mediators (SPMs);Fatty acid metabolism;Linoleate metabolism;Urea cycle and metabolism of arginine, proline, glutamate, aspartate and asparagine;Arachidonic acid metabolism (Consensus)

Intolerance Scores

• loftool: 0.582
• rvis_EVS: -0.12
• rvis_percentile_EVS: 44.89

Haploinsufficiency Scores

• pHI: 0.142
• hipred: N
• hipred_score: 0.231
• ghis: 0.526

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.989

Mouse Genome Informatics

• Gene name: Gpx4
• Phenotype: nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); reproductive system phenotype; normal 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); embryo phenotype; liver/biliary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); cellular phenotype; homeostasis/metabolism phenotype; growth/size/body region phenotype

Zebrafish Information Network

• Gene name: gpx4b
• Affected structure: caudal fin
• Phenotype tag: abnormal
• Phenotype quality: decreased size

Gene ontology

• Biological process: chromatin organization;phospholipid metabolic process;glutathione metabolic process;response to oxidative stress;multicellular organism development;spermatogenesis;aging;lipoxygenase pathway;response to estradiol;long-chain fatty acid biosynthetic process;regulation of inflammatory response;protein polymerization;oxidation-reduction process;cellular oxidant detoxification;negative regulation of ferroptosis
• Cellular component: nucleus;nuclear envelope;nucleoplasm;mitochondrion;cytosol;protein-containing complex;extracellular exosome
• Molecular function: peroxidase activity;glutathione peroxidase activity;protein binding;selenium binding;identical protein binding;phospholipid-hydroperoxide glutathione peroxidase activity