SETDB1

Chr 1

SET domain bifurcated histone lysine methyltransferase 1

Also known as: ESET, H3-K9-HMTase4, KG1T, KMT1E, TDRD21

NCBI Gene: 9869 ENSG00000143379 UniProt: Q15047

This gene encodes a histone methyltransferase which regulates histone methylation, gene silencing, and transcriptional repression. This gene has been identified as a target for treatment in Huntington Disease, given that gene silencing and transcription dysfunction likely play a role in the disease pathogenesis. Alternatively spliced transcript variants of this gene have been described.[provided by RefSeq, Jun 2011]

GeneReviews Research

GeneReviews ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.20

Clinical Summary— SETDB1

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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.

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ClinVar Variants

39 VUS of 107 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SETDB1

Authoritative clinical overview · Recommended first read

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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?

0.20LOEUF

pLI 1.000

Z-score 6.69

OE 0.11 (0.06–0.20)

Highly constrained

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

Missense Constraint?

4.01Z-score

OE missense 0.59 (0.54–0.63)

434 obs / 741.0 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.11 (0.06–0.20)

0≤0.351.4

Missense OE?0.59 (0.54–0.63)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 7 / 65.4Missense obs/exp: 434 / 741.0Syn Z: -0.38

This gene — mechanism propensity

0.2598th %ile

GOF

0.2696th %ile

LOF

0.78top 5%

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

LOFprediction above median · LOEUF 0.20

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

ClinVar Variant Classifications

107 submitted variants in ClinVar

ClinVar

Classification Summary

VUS39

Likely Benign18

Benign5

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	2	37	0	0	39
Likely Benign	0	3	4	11	18
Benign	1	2	0	2	5
Total	3	42	4	13	62

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

View in ClinVar →

14 pathogenic / likely-pathogenic (of 17) ClinVar copy-number / structural variants overlap SETDB1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →