HIF3A
protein-codinghypoxia inducible factor 3 subunit alpha, the group of Basic helix-loop-helix proteins|PAS domain containing
Gene summary
The protein encoded by this gene is the alpha-3 subunit of one of several alpha/beta-subunit heterodimeric transcription factors that regulate many adaptive responses to low oxygen tension (hypoxia). The alpha-3 subunit lacks the transactivation domain found in factors containing either the alpha-1 or alpha-2 subunits. It is thought that factors containing the alpha-3 subunit are negative regulators of hypoxia-inducible gene expression. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Mar 2011]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~46.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
No GenCC data available for this gene.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to HIF3A variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_152795.4. 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 | 1 | 6 | 1 | 8 | ||
| missense | 127 | 10 | 1 | 138 | ||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 2 | 2 | ||||
| Total | 0 | 0 | 130 | 16 | 2 | 148 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_690008.2 | 15 | MANE Select | |
| Ensembl | ENSP00000366898.3 | 15 | MANE Select | |
| RefSeq | NP_071907.4 | 13 | Standard | |
| RefSeq | NP_690007.1 | 15 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Focal Adhesion-PI3K-Akt-mTOR-signaling pathway
- Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha
- Regulation of gene expression by Hypoxia-inducible Factor
- Regulation of Hypoxia-inducible Factor (HIF) by oxygen
- Cellular response to hypoxia
Biological Process
- angiogenesis
- regulation of transcription by RNA polymerase II
- transcription by RNA polymerase II
- apoptotic process
- post-translational protein modification
Molecular Function
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA binding
- protein dimerization activity
Cellular Component
- nucleus
- nucleoplasm
- mitochondrion
- cytosol
- plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000377670
- Coding exons
- 15
- Length
- 46388
- Individuals with no LoFs
- 125715
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 33
- Defined
- 125748
- p
- 0.000131
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.757 | 370 | 413 | 0.895 | 0.0000255 | 4252 |
| Missense (PolyPhen) | 126 | 179.1 | 0.70352 | 1798 | ||
| Synonymous | -0.200 | 182 | 179 | 1.02 | 0.0000116 | 1427 |
| Loss of Function | 3.19 | 10 | 28.3 | 0.353 | 0.00000129 | 333 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00018 | 0.00018 | rare |
| Latino/Admixed American | 0.00016 | 0.00014 | rare |
| Ashkenazi Jewish | 0.00010 | 0.000099 | rare |
| East Asian | 0.00022 | 0.00022 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00014 | 0.00014 | rare |
| South Asian | 0.00013 | 0.00013 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Acts as a transcriptional regulator in adaptive response to low oxygen tension. Acts as a regulator of hypoxia-inducible gene expression (PubMed:11573933, PubMed:16126907, PubMed:19694616, PubMed:20416395, PubMed:21069422). Functions as an inhibitor of angiogenesis in hypoxic cells of the cornea. Plays a role in the development of the cardiorespiratory system. May also be involved in apoptosis (By similarity). {ECO:0000250|UniProtKB:Q0VBL6, ECO:0000269|PubMed:11573933, ECO:0000269|PubMed:16126907, ECO:0000269|PubMed:19694616, ECO:0000269|PubMed:20416395, ECO:0000269|PubMed:21069422}.; FUNCTION: Isoform 3: Attenuates the ability of transcription factor HIF1A to bind to hypoxia-responsive elements (HRE) located within the enhancer/promoter of hypoxia-inducible target genes and hence inhibits HRE-driven transcriptional activation. {ECO:0000269|PubMed:19694616, ECO:0000269|PubMed:20416395, ECO:0000269|PubMed:21069422}.; FUNCTION: Isoform 5: Attenuates the ability of transcription factor HIF1A to bind to hypoxia-responsive elements (HRE) located within the enhancer/promoter of hypoxia-inducible target genes and hence inhibits HRE-driven transcriptional activation. {ECO:0000269|PubMed:21069422}.;
Recessive Scores
- pRec
- 0.154
Intolerance Scores
- LoFtool
- 0.849
- RVIS EVS
- -0.33
- RVIS percentile EVS
- 30.9
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.864
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |