HSPA8

Chr 11

heat shock protein family A (Hsp70) member 8

Also known as: HEL-33, HEL-S-72p, HSC54, HSC70, HSC71, HSP71, HSP73, HSPA10

NCBI Gene: 3312 ENSG00000109971 UniProt: P11142 OMIM: 600816

The HSPA8 protein is a constitutively expressed heat shock cognate protein that functions as a molecular chaperone, facilitating protein folding, chaperone-mediated autophagy, and clathrin-coated vesicle uncoating. Mutations cause autosomal dominant neurodevelopmental disorders with intellectual disability and neurological features. This gene is highly constrained against loss-of-function variants, indicating that such mutations are likely to cause severe developmental consequences.

OMIM ResearchSummary from RefSeq, UniProt

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]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

204

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.20

LOEUF· LoF intol.

LOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.20LOEUF

pLI 0.999

Z-score 4.31

OE 0.04 (0.01–0.20)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

4.46Z-score

OE missense 0.33 (0.29–0.39)

119 obs / 355.7 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.04 (0.01–0.20)

0≤0.351.4

Missense OE?0.33 (0.29–0.39)

0≤0.61.4

Synonymous OE?1.82

0≤1.21.6

LoF obs/exp: 1 / 23.6Missense obs/exp: 119 / 355.7Syn Z: -7.09

Background carrier burden — how many people carry a rare variant somewhere in HSPA8?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 490

377 rare PASS variants

Rare truncating (LoF)

1 in 6,100

25 rare PASS variants

Rare synonymous (reference)

1 in 67

456 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for HSPA8. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 560	1 in 9,300
South Asian	~43k	1 in 450	≈ 1 in 14,000
Remaining (unassigned)	~30k	1 in 300	≈ 1 in 15,000
European (Finnish)	~27k	1 in 1,600	1 in 3,800
Admixed American	~22k	1 in 340	1 in 1,700
African / African American	~21k	1 in 550	≈ 1 in 10,000
East Asian	~20k	1 in 290	1 in 2,300
Ashkenazi Jewish	~13k	1 in 300	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 480	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 8 coding exons well covered in gnomAD exomes and genomes.? see exons ↓