DNAJA3

Chr 16

DnaJ heat shock protein family (Hsp40) member A3

Also known as: HCA57, TID1, Tid1-L, Tid1-S, hTID-1

NCBI Gene: 9093 ENSG00000103423 UniProt: Q96EY1

This gene encodes a mitochondrial-localized DNAJ/Hsp40 co-chaperone protein that stimulates Hsp70 ATPase activity and modulates apoptotic signaling pathways, including cytochrome C release and caspase 3 activation. Mutations cause autosomal recessive spinal muscular atrophy with congenital bone fractures, a severe early-onset neuromuscular disorder affecting motor neurons and bone development. The gene is highly constrained against loss-of-function variation (LOEUF 0.59), reflecting its essential cellular functions.

ResearchSummary from RefSeq, UniProt

This gene encodes a member of the DNAJ/Hsp40 protein family. DNAJ/Hsp40 proteins stimulate the ATPase activity of Hsp70 chaperones and play critical roles in protein folding, degradation, and multimeric complex assembly. The encoded protein is localized to mitochondria and mediates several cellular processes including proliferation, survival and apoptotic signal transduction. The encoded protein also plays a critical role in tumor suppression through interactions with oncogenic proteins including ErbB2 and the p53 tumor suppressor protein. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Aug 2011]

ResearchGenerating clinical summary…

DNmechanismLOEUF 0.59

Clinical Summary— DNAJA3

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.

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ClinVar Variants

98 VUS of 124 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.59LOEUF

pLI 0.010

Z-score 3.09

OE 0.33 (0.19–0.59)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

-0.39Z-score

OE missense 1.06 (0.97–1.17)

307 obs / 288.5 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.33 (0.19–0.59)

0≤0.351.4

Missense OE?1.06 (0.97–1.17)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 8 / 24.5Missense obs/exp: 307 / 288.5Syn Z: -0.38

This gene — mechanism propensity

0.76top 25%

GOF

0.6345th %ile

LOF

0.3258th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction 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

124 submitted variants in ClinVar

ClinVar

Classification Summary

VUS98

Likely Benign6

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	98	98
Likely Benign	6	6
Benign	0	0
Total	104	104

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

View in ClinVar →

31 pathogenic / likely-pathogenic (of 43) ClinVar copy-number / structural variants overlap DNAJA3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →