SETDB1

protein-coding

SET domain bifurcated histone lysine methyltransferase 1, the group of Lysine methyltransferases|Tudor domain containing|Methyl-CpG binding domain containing|SET domain containing

Gene summary

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]

MANE transcript

NM_001366418.1

Inheritance

—

ClinVar variants

U:65B:18

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.11

Max pathogenic AF

—

Genomic locus

chr1:150,926,263-150,964,744

External References & Databases

Ensembl (ENSG00000143379)

Transcript & Mutation Effects

hg38 • Region Span ~38.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SETDB1 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 37

not providedTotal: 29

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001366418.1. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	11 clinvar	2 clinvar	16
missense			50 clinvar	3 clinvar	2 clinvar	55
nonsense			1 clinvar			1
start loss						0
frameshift			3 clinvar			3
splice donor/acceptor (+/-2bp)			8 clinvar			8
Total	0	0	65	14	4	83

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 56 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001366418.1	RefSeq	NP_001353347.1	21	MANE Select
ENST00000692827.1	Ensembl	ENSP00000509425.1	21	MANE Select
NM_001145415.2	RefSeq	NP_001138887.1	21	Standard
NM_001243491.2	RefSeq	NP_001230420.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Lysine degradation - Homo sapiens (human)
Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human)
Histone Modifications
PKMTs methylate histone lysines
Chromatin modifying enzymes

Biological Process

Ras protein signal transduction
response to vitamin
histone lysine methylation
response to ethanol
positive regulation of methylation-dependent chromatin silencing

Molecular Function

DNA binding
chromatin binding
protein binding
zinc ion binding
histone-lysine N-methyltransferase activity

Cellular Component

nucleus
nucleoplasm
chromosome
cytosol
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000271640
Coding exons: 21
Length: 38475
Individuals with no LoFs: 125736
Homozygous LoFs: 0
Heterozygous LoFs: 12
Defined: 125748
p: 0.0000477

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.01	434	741	0.586	0.0000424	8483
Missense (PolyPhen)		120	350.29	0.34257		4030
Synonymous	-0.378	275	267	1.03	0.0000141	2536
Loss of Function	6.69	7	65.4	0.107	0.00000402	707

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000070	0.000070	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Histone methyltransferase that specifically trimethylates 'Lys-9' of histone H3. H3 'Lys-9' trimethylation represents a specific tag for epigenetic transcriptional repression by recruiting HP1 (CBX1, CBX3 and/or CBX5) proteins to methylated histones. Mainly functions in euchromatin regions, thereby playing a central role in the silencing of euchromatic genes. H3 'Lys-9' trimethylation is coordinated with DNA methylation. Probably forms a complex with MBD1 and ATF7IP that represses transcription and couples DNA methylation and histone 'Lys-9' trimethylation. Its activity is dependent on MBD1 and is heritably maintained through DNA replication by being recruited by CAF-1. SETDB1 is targeted to histone H3 by TRIM28/TIF1B, a factor recruited by KRAB zinc-finger proteins. Probably forms a corepressor complex required for activated KRAS-mediated promoter hypermethylation and transcriptional silencing of tumor suppressor genes (TSGs) or other tumor-related genes in colorectal cancer (CRC) cells (PubMed:24623306). Also required to maintain a transcriptionally repressive state of genes in undifferentiated embryonic stem cells (ESCs) (PubMed:24623306). Associates at promoter regions of tumor suppressor genes (TSGs) leading to their gene silencing (PubMed:24623306). The SETDB1-TRIM28-ZNF274 complex may play a role in recruiting ATRX to the 3'-exons of zinc-finger coding genes with atypical chromatin signatures to establish or maintain/protect H3K9me3 at these transcriptionally active regions (PubMed:27029610). {ECO:0000269|PubMed:12869583, ECO:0000269|PubMed:14536086, ECO:0000269|PubMed:15327775, ECO:0000269|PubMed:17952062, ECO:0000269|PubMed:24623306, ECO:0000269|PubMed:27029610}.;

Intolerance Scores

LoFtool: 0.0153
RVIS EVS: -1.46
RVIS percentile EVS: 3.81

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 1.00

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium