HSBP1

Chr 16

heat shock factor binding protein 1

Also known as: NPC-A-13

NCBI Gene: 3281 ENSG00000230989 UniProt: O75506 OMIM: 604553

Heat shock factor binding protein 1 (HSBP1) negatively regulates the cellular heat shock response by binding to and inhibiting the DNA-binding activity of heat shock factor 1 (HSF1), a key transcription factor that controls stress response genes. Biallelic mutations in HSBP1 cause neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed puberty, inherited in an autosomal recessive pattern. The gene shows tolerance to loss-of-function variants (LOEUF 1.402), and the disorder primarily affects the nervous system with additional features including ocular abnormalities and growth/developmental delays.

OMIM ResearchSummary from RefSeq, UniProt

The heat-shock response is elicited by exposure of cells to thermal and chemical stress and through the activation of HSFs (heat shock factors) results in the elevated expression of heat-shock induced genes. Heat shock factor binding protein 1 (HSBP1), is a 76-amino-acid protein that binds to heat shock factor 1(HSF1), which is a transcription factor involved in the HS response. During HS response, HSF1 undergoes conformational transition from an inert non-DNA-binding monomer to active functional trimers. HSBP1 is nuclear-localized and interacts with the active trimeric state of HSF1 to negatively regulate HSF1 DNA-binding activity. Overexpression of HSBP1 in mammalian cells represses the transactivation activity of HSF1. When overexpressed in C.elegans HSBP1 has severe effects on survival of the animals after thermal and chemical stress consistent with a role of HSBP1 as a negative regulator of heat shock response. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.40

Clinical Summary— HSBP1

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.31) despite low pLI — interpret in context.

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ClinVar Variants

9 VUS of 19 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.40LOEUF

pLI 0.234

Z-score 1.14

OE 0.31 (0.11–1.40)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.58Z-score

OE missense 0.73 (0.54–1.01)

28 obs / 38.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.31 (0.11–1.40)

0≤0.351.4

Missense OE?0.73 (0.54–1.01)

0≤0.61.4

Synonymous OE?1.23

0≤1.21.6

LoF obs/exp: 1 / 3.2Missense obs/exp: 28 / 38.1Syn Z: -0.68

This gene — mechanism propensity

0.81top 10%

GOF

0.74top 25%

LOF

0.2677th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

19 submitted variants in ClinVar

ClinVar

Classification Summary

VUS9

Likely Benign1

Benign6

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	9	0	9
Likely Benign	1	0	1
Benign	0	6	6
Total	10	6	16

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

41 pathogenic / likely-pathogenic (of 67) ClinVar copy-number / structural variants overlap HSBP1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →