SETD5

Chr 3AD

SET domain containing 5

ENSG00000168137 UniProt: Q9C0A6 OMIM: 615743

The protein is predicted to function as a histone methyltransferase based on its SET domain. Mutations cause intellectual developmental disorder, autosomal dominant 23 through a loss-of-function mechanism. The condition follows an autosomal dominant inheritance pattern.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Chromatin regulator required for brain development: acts as a regulator of RNA elongation rate, thereby regulating neural stem cell (NSC) proliferation and synaptic transmission. May act by mediating trimethylation of 'Lys-36' of histone H3 (H3K36me3), which is essential to allow on-time RNA elongation dynamics. Also monomethylates 'Lys-9' of histone H3 (H3K9me1) in vitro. The relevance of histone methyltransferase activity is however subject to discussion

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.231 OMIM phenotype

Clinical Summary— SETD5

🧬

Gene-Disease Validity (ClinGen)

syndromic complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

💊

Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.23LOEUF

pLI 1.000

Z-score 6.70

OE 0.13 (0.08–0.23)

Highly constrained

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

Missense Constraint?

1.13Z-score

OE missense 0.89 (0.83–0.94)

683 obs / 771.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.13 (0.08–0.23)

0≤0.351.4

Missense OE?0.89 (0.83–0.94)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 9 / 69.1Missense obs/exp: 683 / 771.5Syn Z: -0.68

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSETD5-related intellectual developmental disorderLOFAD

This gene — mechanism propensity

0.2399th %ile

GOF

0.2098th %ile

LOF

0.88top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · LOEUF 0.23 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFHaploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References