EGLN3

egl-9 family hypoxia inducible factor 3

Basic information

Region (hg38): 14:33924226-34462774

Links

ENSG00000129521 ∙ NCBI:112399 ∙ OMIM:606426 ∙ HGNC:14661 ∙ Uniprot:Q9H6Z9 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

No genCC data.

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the EGLN3 gene.

• not provided (2 variants)
• Inborn genetic diseases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the EGLN3 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	1
missense			1		1	2
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding						0
Total	0	0	1	0	2

Variants in EGLN3

This is a list of pathogenic ClinVar variants found in the EGLN3 region.

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

Position	Type	Phenotype	Significance	ClinVar
14-33929099-T-C			Benign (Dec 31, 2019)
14-33929149-T-C		not specified	Uncertain significance (Oct 16, 2023)
14-33929173-A-G		not specified	Uncertain significance (May 23, 2023)
14-33950541-C-T			Benign (Dec 31, 2019)
14-33950611-T-C		not specified	Uncertain significance (Jan 08, 2024)
14-33950730-C-T		not specified	Uncertain significance (Oct 10, 2023)
14-34435244-TGG-T		Spastic paraplegia 90B, autosomal recessive	Pathogenic (Dec 07, 2023)
14-34435265-G-A		SPTSSA-related disorder • Spastic paraplegia 90A, autosomal dominant	Conflicting classifications of pathogenicity (Dec 07, 2023)
14-34462156-A-C		not specified	Uncertain significance (Oct 20, 2021)
14-34462156-A-T		not specified	Uncertain significance (Jan 04, 2022)
14-34462198-T-C		not specified	Uncertain significance (Aug 02, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
EGLN3	protein_coding	protein_coding	ENST00000250457	5	538544

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00948	0.945	125727	0	21	125748	0.0000835

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.72	86	144	0.598	0.00000734	1551
Missense in Polyphen		17	40.116	0.42377		422
Synonymous	-0.804	69	61.0	1.13	0.00000319	479
Loss of Function	1.73	5	11.3	0.443	4.79e-7	129

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000623	0.0000615
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.000556	0.000554
European (Non-Finnish)	0.0000442	0.0000439
Middle Eastern	0.00	0.00
South Asian	0.0000327	0.0000327
Other	0.000327	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A. Also hydroxylates HIF2A. Has a preference for the CODD site for both HIF1A and HIF2A. Hydroxylation on the NODD site by EGLN3 appears to require prior hydroxylation on the CODD site. Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Under hypoxic conditions, the hydroxylation reaction is attenuated allowing HIFs to escape degradation resulting in their translocation to the nucleus, heterodimerization with HIF1B, and increased expression of hypoxy-inducible genes. EGLN3 is the most important isozyme in limiting physiological activation of HIFs (particularly HIF2A) in hypoxia. Also hydroxylates PKM in hypoxia, limiting glycolysis. Under normoxia, hydroxylates and regulates the stability of ADRB2. Regulator of cardiomyocyte and neuronal apoptosis. In cardiomyocytes, inhibits the anti-apoptotic effect of BCL2 by disrupting the BAX-BCL2 complex. In neurons, has a NGF-induced proapoptotic effect, probably through regulating CASP3 activity. Also essential for hypoxic regulation of neutrophilic inflammation. Plays a crucial role in DNA damage response (DDR) by hydroxylating TELO2, promoting its interaction with ATR which is required for activation of the ATR/CHK1/p53 pathway. Target proteins are preferentially recognized via a LXXLAP motif. {ECO:0000269|PubMed:11595184, ECO:0000269|PubMed:12181324, ECO:0000269|PubMed:16098468, ECO:0000269|PubMed:19584355, ECO:0000269|PubMed:20849813, ECO:0000269|PubMed:20978507, ECO:0000269|PubMed:21317538, ECO:0000269|PubMed:21483450, ECO:0000269|PubMed:21575608, ECO:0000269|PubMed:21620138, ECO:0000269|PubMed:22797300}.
• Pathway: Renal cell carcinoma - Homo sapiens (human);HIF-1 signaling pathway - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);The oncogenic action of Succinate;The oncogenic action of Fumarate;Type 2 papillary renal cell carcinoma;Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha;Regulation of Hypoxia-inducible Factor (HIF) by oxygen;Cellular response to hypoxia;Cellular responses to stress;HIF-2-alpha transcription factor network;Hypoxic and oxygen homeostasis regulation of HIF-1-alpha;Cellular responses to external stimuli;HIF-1-alpha transcription factor network (Consensus)

Recessive Scores

• pRec: 0.215

Intolerance Scores

• loftool: 0.474
• rvis_EVS: -0.07
• rvis_percentile_EVS: 48.12

Haploinsufficiency Scores

• pHI: 0.804
• hipred: Y
• hipred_score: 0.728
• ghis: 0.479

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.940

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Egln3
• Phenotype: cellular phenotype; homeostasis/metabolism phenotype; craniofacial phenotype; muscle phenotype; endocrine/exocrine gland 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); growth/size/body region phenotype; immune system phenotype; vision/eye 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); limbs/digits/tail 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); normal phenotype; reproductive system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; liver/biliary system phenotype

Gene ontology

• Biological process: response to hypoxia;apoptotic process;activation of cysteine-type endopeptidase activity involved in apoptotic process;cellular response to DNA damage stimulus;protein hydroxylation;peptidyl-proline hydroxylation to 4-hydroxy-L-proline;regulation of cell population proliferation;regulation of neuron apoptotic process;oxidation-reduction process;regulation of transcription from RNA polymerase II promoter in response to hypoxia
• Cellular component: nucleus;nucleoplasm;cytoplasm;cytosol
• Molecular function: iron ion binding;protein binding;2-oxoglutarate-dependent dioxygenase activity;L-ascorbic acid binding;peptidyl-proline 4-dioxygenase activity