DHX33

Chr 17

DEAH-box helicase 33

Also known as: DDX33

NCBI Gene: 56919 ENSG00000005100 UniProt: Q9H6R0 OMIM: 614405

This gene encodes DHX33, a DEAD-box RNA helicase that stimulates ribosomal RNA transcription, promotes ribosome assembly during translation initiation, and functions as a cytoplasmic double-stranded RNA sensor for innate immune signaling. Mutations cause autosomal recessive intellectual developmental disorder with seizures and dysmorphic facies, typically presenting in early childhood. The gene shows low constraint against loss-of-function variants (pLI near 0), consistent with the recessive inheritance pattern observed clinically.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the DEAD box protein family. The DEAD box proteins are characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a number of cellular processes involving alteration of RNA secondary structure such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of this DEAD box protein family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2010]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.68

Clinical Summary— DHX33

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

108 VUS of 125 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.68LOEUF

pLI 0.000

Z-score 2.98

OE 0.43 (0.29–0.68)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.46Z-score

OE missense 0.94 (0.86–1.02)

397 obs / 423.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.43 (0.29–0.68)

0≤0.351.4

Missense OE?0.94 (0.86–1.02)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 14 / 32.3Missense obs/exp: 397 / 423.8Syn Z: 0.24

This gene — mechanism propensity

0.76top 25%

GOF

0.5759th %ile

LOF

0.3453th %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

125 submitted variants in ClinVar

ClinVar

Classification Summary

VUS108

Likely Benign4

108

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	108	108
Likely Benign	4	4
Benign	0	0
Total	112	112

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

View in ClinVar →

23 pathogenic / likely-pathogenic (of 30) ClinVar copy-number / structural variants overlap DHX33 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →