HSPA9
protein-codingheat shock protein family A (Hsp70) member 9, the group of Heat shock 70kDa proteins|Small nucleolar RNA protein coding host genes
Gene summary
This gene encodes a member of the heat shock protein 70 gene family. The encoded protein is primarily localized to the mitochondria but is also found in the endoplasmic reticulum, plasma membrane and cytoplasmic vesicles. This protein is a heat-shock cognate protein. This protein plays a role in cell proliferation, stress response and maintenance of the mitochondria. A pseudogene of this gene is found on chromosome 2.[provided by RefSeq, May 2010]
- HSPA9B
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~21.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0008422
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0014801
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0014801
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0008422
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0014801
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0014801
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0014801
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0016828
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008422
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0008422
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Craniofacial; Dermatologic; Gastrointestinal; Hematologic; Musculoskeletal
Intervention: Cardiovascular; Hematologic; Renal
Rationale: Individuals with anemia have been described with anemia requiring RBC transfusions in some individuals, and awareness may allow for surveillance and prompt management; EVEN-plus syndrome may involve congenital anomalies (eg, cardiac anomalies) that require early identification and interventions for management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to HSPA9 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_004134.7. 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 | 21 | 1 | 24 | ||
| missense | 2 | 1 | 79 | 6 | 88 | |
| nonsense | 1 | 2 | 3 | |||
| start loss | 0 | |||||
| frameshift | 1 | 1 | 2 | |||
| splice donor/acceptor (+/-2bp) | 1 | 3 | 4 | |||
| Total | 4 | 3 | 86 | 27 | 1 | 121 |
Highest pathogenic variant AF is 0.00014574149
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_004125.3 | 17 | MANE Select | |
| Ensembl | ENSP00000297185.3 | 17 | MANE Select | |
| Ensembl | ENSP00000421311.2 | 12 | Standard | |
| Ensembl | ENSP00000423759.2 | 16 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| hspa9 | Danio rerio | Structure: blood cell Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- RNA degradation - Homo sapiens (human)
- Tuberculosis - Homo sapiens (human)
- Parkin-Ubiquitin Proteasomal System pathway
- Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation
- Regulation of HSF1-mediated heat shock response
Biological Process
- response to unfolded protein
- iron-sulfur cluster assembly
- erythrocyte differentiation
- cellular response to heat
- cellular response to unfolded protein
Molecular Function
- RNA binding
- protein binding
- ATP binding
- ATPase activity
- heat shock protein binding
Cellular Component
- nucleolus
- cytoplasm
- mitochondrion
- mitochondrial matrix
- focal adhesion
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000297185
- Coding exons
- 17
- Length
- 20563
- Individuals with no LoFs
- 125702
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 46
- Defined
- 125748
- p
- 0.000183
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.04 | 312 | 368 | 0.848 | 0.0000200 | 4447 |
| Missense (PolyPhen) | 87 | 148.71 | 0.58503 | 2008 | ||
| Synonymous | -0.267 | 133 | 129 | 1.03 | 0.00000677 | 1346 |
| Loss of Function | 4.74 | 6 | 37.2 | 0.161 | 0.00000225 | 420 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00018 | 0.00018 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0.00018 | 0.00018 | rare |
| European (Non-Finnish) | 0.00028 | 0.00028 | rare |
| South Asian | 0.000098 | 0.000098 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Chaperone protein which plays an important role in mitochondrial iron-sulfur cluster (ISC) biogenesis. Interacts with and stabilizes ISC cluster assembly proteins FXN, NFU1, NFS1 and ISCU (PubMed:26702583). Regulates erythropoiesis via stabilization of ISC assembly (PubMed:21123823, PubMed:26702583). May play a role in the control of cell proliferation and cellular aging (By similarity). {ECO:0000250|UniProtKB:P38647, ECO:0000269|PubMed:21123823, ECO:0000269|PubMed:26702583}.;
- Disease
- DISEASE: Anemia, sideroblastic, 4 (SIDBA4) [MIM:182170]: A form of sideroblastic anemia, a bone marrow disorder defined by the presence of pathologic iron deposits in erythroblast mitochondria. Sideroblastic anemia is characterized by anemia of varying severity, hypochromic peripheral erythrocytes, systemic iron overload secondary to chronic ineffective erythropoiesis, and the presence of bone marrow ringed sideroblasts. Sideroblasts are characterized by iron-loaded mitochondria clustered around the nucleus. SIDBA4 has been reported to be inherited as an autosomal recessive disease, with a pseudodominant pattern of inheritance in some families. {ECO:0000269|PubMed:26491070}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Even-plus syndrome (EVPLS) [MIM:616854]: An autosomal recessive syndrome characterized by epiphyseal and vertebral dysplasia, prenatal-onset short stature, a distinct craniofacial phenotype with microtia, a flat facial profile with flat nose and triangular nares, cardiac malformations, and additional findings such as anal atresia, hypodontia, aplasia cutis, and others. {ECO:0000269|PubMed:26598328}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.734
Intolerance Scores
- LoFtool
- 0.423
- RVIS EVS
- -0.85
- RVIS percentile EVS
- 11.06
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.835
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |