DROSHA

Chr 5

drosha ribonuclease III

Also known as: ETOHI2, HSA242976, RANSE3L, RN3, RNASE3L, RNASEN

NCBI Gene: 29102 ENSG00000113360 UniProt: Q9NRR4 OMIM: 608828

The protein is a ribonuclease III enzyme that cleaves primary microRNA transcripts in the nucleus as part of the microprocessor complex, catalyzing the initial step of microRNA biogenesis by generating precursor miRNAs. Mutations cause neurodevelopmental disorders with intellectual disability, growth abnormalities, and various congenital malformations, following an autosomal dominant inheritance pattern. The gene is highly constrained against loss-of-function variation (LOEUF 0.347), reflecting its essential role in cellular regulation through microRNA processing.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a ribonuclease (RNase) III double-stranded RNA-specific ribonuclease and subunit of the microprocessor protein complex, which catalyzes the initial processing step of microRNA (miRNA) synthesis. The encoded protein cleaves the stem loop structure from the primary microRNA (pri-miRNA) in the nucleus, yielding the precursor miRNA (pre-miRNA), which is then exported to the cytoplasm for further processing. In a human cell line lacking a functional copy of this gene, canonical miRNA synthesis is reduced. Somatic mutations in this gene have been observed in human patients with kidney cancer. [provided by RefSeq, Sep 2016]

GeneReviews OMIM ResearchGenerating clinical summary…

LOEUF 0.35

Clinical Summary— DROSHA

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.24) despite low pLI — interpret in context.

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ClinVar Variants

9 unique Pathogenic / Likely Pathogenic· 138 VUS of 262 total submissions

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GeneReview available — DROSHA

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.35LOEUF

pLI 0.093

Z-score 6.45

OE 0.24 (0.17–0.35)

Highly constrained

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

Missense Constraint?

3.98Z-score

OE missense 0.60 (0.56–0.65)

469 obs / 782.7 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.24 (0.17–0.35)

0≤0.351.4

Missense OE?0.60 (0.56–0.65)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 20 / 83.7Missense obs/exp: 469 / 782.7Syn Z: 0.88

ClinVar Variant Classifications

262 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9

VUS138

Likely Benign50

Benign15

Pathogenic

138

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	8	1	0	0	9
Likely Pathogenic	0	0	0	0	0
VUS	4	134	0	0	138
Likely Benign	0	7	11	32	50
Benign	0	5	2	8	15
Total	12	147	13	40	212

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

View in ClinVar →

30 pathogenic / likely-pathogenic (of 35) ClinVar copy-number / structural variants overlap DROSHA — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →