HSPH1

protein-coding

heat shock protein family H (Hsp110) member 1, the group of Heat shock 70kDa proteins

Gene summary

This gene encodes a member of the heat shock protein 70 family of proteins. The encoded protein functions as a nucleotide exchange factor for the molecular chaperone heat shock cognate 71 kDa protein (Hsc70). In addition, this protein plays a distinct but related role as a holdase that inhibits the aggregation of misfolded proteins, including the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Elevated expression of this protein has been observed in numerous human cancers. [provided by RefSeq, Mar 2017]

MANE transcript

NM_006644.4

Inheritance

—

ClinVar variants

U:99B:11

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.13

Max pathogenic AF

—

Genomic locus

chr13:31,134,973-31,162,388

External References & Databases

Ensembl (ENSG00000120694)

Transcript & Mutation Effects

hg38 • Region Span ~27.4 kb

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GenCC 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 HSPH1 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 85

not providedTotal: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006644.4. 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			4 clinvar	3 clinvar	1 clinvar	8
missense			88 clinvar	6 clinvar	1 clinvar	95
nonsense			2 clinvar			2
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	0	0	99	9	2	110

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 46 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006644.4	RefSeq	NP_006635.2	18	MANE Select
ENST00000320027.10	Ensembl	ENSP00000318687.5	18	MANE Select
NM_001286503.2	RefSeq	NP_001273432.1	17	Standard
NM_001286504.1	RefSeq	NP_001273433.1	18	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Protein processing in endoplasmic reticulum - Homo sapiens (human)
Cellular response to heat stress
HSF1 activation
Attenuation phase
HSF1-dependent transactivation

Biological Process

receptor-mediated endocytosis
response to unfolded protein
positive regulation of MHC class I biosynthetic process
regulation of catalytic activity
chaperone cofactor-dependent protein refolding

Molecular Function

adenyl-nucleotide exchange factor activity
protein binding
ATP binding
alpha-tubulin binding

Cellular Component

extracellular region
nucleus
nucleoplasm
cytoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000320027
Coding exons: 18
Length: 25764
Individuals with no LoFs: 125735
Homozygous LoFs: 0
Heterozygous LoFs: 10
Defined: 125745
p: 0.0000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.72	344	446	0.771	0.0000216	5695
Missense (PolyPhen)		110	185.48	0.59304		2393
Synonymous	-1.36	179	157	1.14	0.00000781	1557
Loss of Function	5.38	6	44.9	0.134	0.00000244	559

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000055	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000063	0.000062	rare
South Asian	0	0.0	absent
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Acts as a nucleotide-exchange factor (NEF) for chaperone proteins HSPA1A and HSPA1B, promoting the release of ADP from HSPA1A/B thereby triggering client/substrate protein release (PubMed:24318877). Prevents the aggregation of denatured proteins in cells under severe stress, on which the ATP levels decrease markedly. Inhibits HSPA8/HSC70 ATPase and chaperone activities (By similarity). {ECO:0000250|UniProtKB:Q60446, ECO:0000250|UniProtKB:Q61699, ECO:0000269|PubMed:24318877}.;

Recessive Scores

pRec: 0.346

Intolerance Scores

LoFtool: 0.503
RVIS EVS: -0.57
RVIS percentile EVS: 18.96

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.533

Gene Damage Prediction

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