HSPA8
protein-codingheat shock protein family A (Hsp70) member 8, the group of Heat shock 70kDa proteins|Spliceosomal P complex|Spliceosomal C complex
Gene summary
This gene encodes a member of the heat shock protein 70 family, which contains both heat-inducible and constitutively expressed members. This protein belongs to the latter group, which are also referred to as heat-shock cognate proteins. It functions as a chaperone, and binds to nascent polypeptides to facilitate correct folding. It also functions as an ATPase in the disassembly of clathrin-coated vesicles during transport of membrane components through the cell. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]
- HSPA10
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~5.7 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 HSPA8 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_006597.6. 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 | 4 | 1 | 4 | 9 | ||
| missense | 30 | 30 | ||||
| nonsense | 1 | 1 | ||||
| start loss | 1 | 1 | ||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 0 | 0 | 38 | 1 | 4 | 43 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_006588.1 | 8 | MANE Select | |
| Ensembl | ENSP00000432083.1 | 8 | MANE Select | |
| RefSeq | NP_694881.1 | 7 | Standard | |
| Ensembl | ENSP00000227378.3 | 8 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| hspa8 | Danio rerio | Structure: ceratohyal cartilage Quality: deformed abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Antigen processing and presentation - Homo sapiens (human)
- Legionellosis - Homo sapiens (human)
- Endocytosis - Homo sapiens (human)
- Longevity regulating pathway - multiple species - Homo sapiens (human)
- Influenza A - Homo sapiens (human)
Biological Process
- mRNA splicing, via spliceosome
- protein folding
- response to unfolded protein
- axo-dendritic transport
- cellular response to starvation
Molecular Function
- G protein-coupled receptor binding
- phosphatidylserine binding
- RNA binding
- protein binding
- ATP binding
Cellular Component
- ubiquitin ligase complex
- Prp19 complex
- extracellular region
- extracellular space
- nucleus
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000534624
- Coding exons
- 8
- Length
- 5742
- Individuals with no LoFs
- 125740
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 7
- Defined
- 125747
- p
- 0.0000278
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 4.46 | 119 | 356 | 0.335 | 0.0000177 | 4258 |
| Missense (PolyPhen) | 25 | 119.64 | 0.20896 | 1612 | ||
| Synonymous | -7.09 | 222 | 122 | 1.82 | 0.00000582 | 1279 |
| Loss of Function | 4.31 | 1 | 23.6 | 0.0424 | 0.00000126 | 291 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000063 | 0.000062 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000047 | 0.000046 | rare |
| European (Non-Finnish) | 0.000053 | 0.000026 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Molecular chaperone implicated in a wide variety of cellular processes, including protection of the proteome from stress, folding and transport of newly synthesized polypeptides, activation of proteolysis of misfolded proteins and the formation and dissociation of protein complexes. Plays a pivotal role in the protein quality control system, ensuring the correct folding of proteins, the re-folding of misfolded proteins and controlling the targeting of proteins for subsequent degradation (PubMed:21150129, PubMed:21148293, PubMed:24732912, PubMed:27916661, PubMed:23018488). This is achieved through cycles of ATP binding, ATP hydrolysis and ADP release, mediated by co-chaperones (PubMed:21150129, PubMed:21148293, PubMed:24732912, PubMed:27916661, PubMed:23018488). The co-chaperones have been shown to not only regulate different steps of the ATPase cycle of HSP70, but they also have an individual specificity such that one co-chaperone may promote folding of a substrate while another may promote degradation (PubMed:21150129, PubMed:21148293, PubMed:24732912, PubMed:27916661, PubMed:23018488). The affinity of HSP70 for polypeptides is regulated by its nucleotide bound state. In the ATP-bound form, it has a low affinity for substrate proteins. However, upon hydrolysis of the ATP to ADP, it undergoes a conformational change that increases its affinity for substrate proteins. HSP70 goes through repeated cycles of ATP hydrolysis and nucleotide exchange, which permits cycles of substrate binding and release. The HSP70-associated co-chaperones are of three types: J- domain co-chaperones HSP40s (stimulate ATPase hydrolysis by HSP70), the nucleotide exchange factors (NEF) such as BAG1/2/3 (facilitate conversion of HSP70 from the ADP-bound to the ATP- bound state thereby promoting substrate release), and the TPR domain chaperones such as HOPX and STUB1 (PubMed:24318877, PubMed:27474739, PubMed:24121476, PubMed:26865365). Acts as a repressor of transcriptional activation. Inhibits the transcriptional coactivator activity of CITED1 on Smad-mediated transcription. Component of the PRP19-CDC5L complex that forms an integral part of the spliceosome and is required for activating pre-mRNA splicing. May have a scaffolding role in the spliceosome assembly as it contacts all other components of the core complex. Binds bacterial lipopolysaccharide (LPS) and mediates LPS-induced inflammatory response, including TNF secretion by monocytes (PubMed:10722728, PubMed:11276205). Participates in the ER- associated degradation (ERAD) quality control pathway in conjunction with J domain-containing co-chaperones and the E3 ligase STUB1 (PubMed:23990462). {ECO:0000269|PubMed:10722728, ECO:0000269|PubMed:11276205, ECO:0000269|PubMed:21148293, ECO:0000269|PubMed:21150129, ECO:0000269|PubMed:23018488, ECO:0000269|PubMed:23990462, ECO:0000269|PubMed:24318877, ECO:0000269|PubMed:24732912, ECO:0000269|PubMed:27474739, ECO:0000269|PubMed:27916661, ECO:0000303|PubMed:24121476, ECO:0000303|PubMed:26865365}.;
Recessive Scores
- pRec
- 0.927
Intolerance Scores
- LoFtool
- 0.0958
- RVIS EVS
- -0.82
- RVIS percentile EVS
- 11.68
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.964
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |