DROSHA

Chr 5

drosha ribonuclease III

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

NCBI Gene: 29102 ENSG00000113360 UniProt: Q9NRR4

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 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 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

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.35

LOEUF· LoF intol.

—

Mechanism

📖

GeneReview available — DROSHA

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 71

1,305 rare PASS variants

Rare truncating (LoF)

1 in 2,200

123 rare PASS variants

Rare synonymous (reference)

1 in 85

566 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for DROSHA. 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 90	1 in 2,100
South Asian	~43k	1 in 49	1 in 2,300
Remaining (unassigned)	~30k	1 in 60	1 in 2,300
European (Finnish)	~27k	1 in 170	1 in 2,600
Admixed American	~22k	1 in 55	1 in 2,500
African / African American	~21k	1 in 52	1 in 1,000
East Asian	~20k	1 in 67	1 in 3,300
Ashkenazi Jewish	~13k	1 in 190	1 in 2,600
Middle Eastern	~2,884	1 in 59	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): 31 of 33 coding exons well covered in gnomAD exomes; exons 7, 15 marginal. Genomes: 31 of 33 (exons 5, 16 below).? see exons ↓