HSPD1

heat shock protein family D (Hsp60) member 1, the group of Chaperonins

Basic information

Region (hg38): 2:197486583-197516737

Previous symbols: [ "SPG13" ]

Links

ENSG00000144381 ∙ NCBI:3329 ∙ OMIM:118190 ∙ HGNC:5261 ∙ Uniprot:P10809 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hereditary spastic paraplegia 13 (Supportive), mode of inheritance: AD
• hypomyelinating leukodystrophy 4 (Supportive), mode of inheritance: AR
• hypomyelinating leukodystrophy 4 (Strong), mode of inheritance: AR
• hereditary spastic paraplegia 13 (Strong), mode of inheritance: AD
• hypomyelinating leukodystrophy 4 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Spastic paraplegia 13, autosomal dominant; Leukodystrophy, hypomyelinating, 4	AD/AR	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Neurologic	10677329; 11898127; 17420924; 18571143

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the HSPD1 gene.

• Spastic paraplegia (163 variants)
• not provided (49 variants)
• Hereditary spastic paraplegia 13 (41 variants)
• not specified (31 variants)
• Hereditary spastic paraplegia (21 variants)
• Hypomyelinating leukodystrophy 4 (7 variants)
• Spastic paraplegia, autosomal dominant (3 variants)
• Inborn genetic diseases (3 variants)
• Hypomyelinating leukodystrophy 4;Hereditary spastic paraplegia 13 (2 variants)
• HSPD1-related condition (2 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HSPD1 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			5	39	8	52
missense	1	3	89	1	1	95
nonsense			1			1
start loss						0
frameshift			2			2
inframe indel			2	1		3
splice donor/acceptor (+/-2bp)						0
splice region			6	9		15
non coding			11	38	16	65
Total	1	3	110	79	25

Variants in HSPD1

This is a list of pathogenic ClinVar variants found in the HSPD1 region.

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

Position	Type	Phenotype	Significance	ClinVar
2-197486587-A-C		Hereditary spastic paraplegia 13	Uncertain significance (Jan 13, 2018)
2-197486592-A-C		Hereditary spastic paraplegia 13	Uncertain significance (Jan 12, 2018)
2-197486662-A-T		Hereditary spastic paraplegia 13	Uncertain significance (Jan 12, 2018)
2-197486733-T-C		Hereditary spastic paraplegia 13	Uncertain significance (Jan 13, 2018)
2-197486925-A-G		Hereditary spastic paraplegia 13	Uncertain significance (Jan 12, 2018)
2-197486990-C-T		Hereditary spastic paraplegia 13	Uncertain significance (Jan 13, 2018)
2-197487027-TA-T		not specified	Likely benign (Dec 05, 2016)
2-197487027-T-TA		Spastic paraplegia, autosomal dominant	Conflicting classifications of pathogenicity (Apr 25, 2018)
2-197487030-A-G		not specified	Uncertain significance (Nov 17, 2023)
2-197487055-GCCACCTCCCATA-G		Spastic paraplegia	Uncertain significance (Sep 20, 2022)
2-197487056-C-A		Spastic paraplegia • Hypomyelinating leukodystrophy 4	Conflicting classifications of pathogenicity (Jan 15, 2024)
2-197487066-T-C		Spastic paraplegia	Uncertain significance (Jul 06, 2022)
2-197487067-A-G		Spastic paraplegia	Likely benign (May 02, 2022)
2-197487067-A-ACCACCTCCCATT		Spastic paraplegia	Likely benign (Dec 09, 2023)
2-197487080-C-G		not specified • Spastic paraplegia • Hereditary spastic paraplegia 13 • Hereditary spastic paraplegia	Benign (Jan 31, 2024)
2-197487080-CCACCCATTG-C		not specified	Uncertain significance (Jun 01, 2023)
2-197487087-T-C		Spastic paraplegia • Hypomyelinating leukodystrophy 4	Likely benign (Sep 16, 2022)
2-197487092-C-T		Spastic paraplegia	Uncertain significance (Jan 20, 2023)
2-197487107-T-A		Spastic paraplegia	Uncertain significance (Aug 24, 2023)
2-197487117-T-C		Spastic paraplegia	Uncertain significance (Jun 29, 2022)
2-197487154-C-G		Spastic paraplegia	Likely benign (Sep 23, 2023)
2-197487154-CAG-C		HSPD1-related disorder	Uncertain significance (May 11, 2023)
2-197487156-G-A		Spastic paraplegia	Likely benign (Jan 12, 2022)
2-197487161-G-A		Hereditary spastic paraplegia 13 • Spastic paraplegia	Conflicting classifications of pathogenicity (Apr 12, 2022)
2-197487183-A-G		Spastic paraplegia	Likely benign (Feb 19, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HSPD1	protein_coding	protein_coding	ENST00000388968	11	30157

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.993	0.00743	125743	0	5	125748	0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.26	195	306	0.637	0.0000150	3736
Missense in Polyphen		33	87.617	0.37664		1246
Synonymous	-0.00899	101	101	1.00	0.00000501	1143
Loss of Function	4.11	2	23.5	0.0853	0.00000118	317

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.0000354	0.0000352
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Chaperonin implicated in mitochondrial protein import and macromolecular assembly. Together with Hsp10, facilitates the correct folding of imported proteins. May also prevent misfolding and promote the refolding and proper assembly of unfolded polypeptides generated under stress conditions in the mitochondrial matrix (PubMed:1346131, PubMed:11422376). The functional units of these chaperonins consist of heptameric rings of the large subunit Hsp60, which function as a back-to-back double ring. In a cyclic reaction, Hsp60 ring complexes bind one unfolded substrate protein per ring, followed by the binding of ATP and association with 2 heptameric rings of the co-chaperonin Hsp10. This leads to sequestration of the substrate protein in the inner cavity of Hsp60 where, for a certain period of time, it can fold undisturbed by other cell components. Synchronous hydrolysis of ATP in all Hsp60 subunits results in the dissociation of the chaperonin rings and the release of ADP and the folded substrate protein (Probable). {ECO:0000269|PubMed:11422376, ECO:0000269|PubMed:1346131, ECO:0000305|PubMed:25918392}.
• Disease: DISEASE: Spastic paraplegia 13, autosomal dominant (SPG13) [MIM:605280]: A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. {ECO:0000269|PubMed:11898127}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Leukodystrophy, hypomyelinating, 4 (HLD4) [MIM:612233]: A severe autosomal recessive hypomyelinating leukodystrophy. Clinically characterized by infantile-onset rotary nystagmus, progressive spastic paraplegia, neurologic regression, motor impairment, profound mental retardation. Death usually occurs within the first two decades of life. {ECO:0000269|PubMed:18571143}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Type I diabetes mellitus - Homo sapiens (human);Legionellosis - Homo sapiens (human);RNA degradation - Homo sapiens (human);Tuberculosis - Homo sapiens (human);Apoptosis-related network due to altered Notch3 in ovarian cancer;Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors;Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways;Gene expression (Transcription);Generic Transcription Pathway;Metabolism of proteins;RNA Polymerase II Transcription;TFAP2A acts as a transcriptional repressor during retinoic acid induced cell differentiation;Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors;Mitochondrial protein import;Validated targets of C-MYC transcriptional activation;Endogenous TLR signaling (Consensus)

Recessive Scores

• pRec: 0.981

Intolerance Scores

• loftool: 0.419
• rvis_EVS: -0.2
• rvis_percentile_EVS: 38.82

Haploinsufficiency Scores

• pHI: 0.979
• hipred: Y
• hipred_score: 0.831
• ghis: 0.618

Essentials

• essential_gene_CRISPR: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.941

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Hspd1
• Phenotype: growth/size/body region phenotype; muscle phenotype; cellular phenotype; embryo phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); reproductive system 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); 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)

Zebrafish Information Network

• Gene name: hspd1
• Affected structure: blastema
• Phenotype tag: abnormal
• Phenotype quality: quality

Gene ontology

• Biological process: response to hypoxia;B cell cytokine production;MyD88-dependent toll-like receptor signaling pathway;positive regulation of T cell mediated immune response to tumor cell;response to ischemia;regulation of transcription by RNA polymerase II;'de novo' protein folding;activation of cysteine-type endopeptidase activity involved in apoptotic process;response to unfolded protein;mitochondrion organization;apoptotic mitochondrial changes;response to cold;response to activity;viral process;response to lipopolysaccharide;positive regulation of interferon-alpha production;positive regulation of interferon-gamma production;positive regulation of interleukin-10 production;positive regulation of interleukin-12 production;positive regulation of interleukin-6 production;response to ATP;cellular response to heat;protein refolding;B cell proliferation;T cell activation;B cell activation;response to cocaine;response to hydrogen peroxide;positive regulation of macrophage activation;positive regulation of apoptotic process;negative regulation of apoptotic process;negative regulation of neuron apoptotic process;response to estrogen;adhesion of symbiont to host;protein import into mitochondrial intermembrane space;isotype switching to IgG isotypes;positive regulation of inflammatory response;protein stabilization;positive regulation of T cell activation;chaperone-mediated protein complex assembly;response to glucocorticoid;protein maturation;interaction with symbiont;negative regulation of apoptotic process in bone marrow cell;cellular response to interleukin-7;negative regulation of reactive oxygen species biosynthetic process;positive regulation of tumor necrosis factor secretion;positive regulation of interleukin-6 secretion
• Cellular component: extracellular space;cytoplasm;mitochondrion;mitochondrial inner membrane;mitochondrial matrix;early endosome;peroxisomal matrix;rough endoplasmic reticulum;Golgi apparatus;cytosol;plasma membrane;clathrin-coated pit;cell surface;membrane;mitochondrial crista;coated vesicle;secretory granule;protein-containing complex;zymogen granule;myelin sheath;membrane raft;lipopolysaccharide receptor complex;extracellular exosome
• Molecular function: lipopolysaccharide binding;protease binding;p53 binding;DNA replication origin binding;single-stranded DNA binding;RNA binding;double-stranded RNA binding;protein binding;ATP binding;high-density lipoprotein particle binding;ATPase activity;enzyme binding;ubiquitin protein ligase binding;apolipoprotein binding;apolipoprotein A-I binding;insulin binding;protein heterodimerization activity;unfolded protein binding;chaperone binding;modification-dependent protein binding