SETDB1

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

Basic information

Region (hg38): 1:150926262-150964744

Links

ENSG00000143379 ∙ NCBI:9869 ∙ OMIM:604396 ∙ HGNC:10761 ∙ Uniprot:Q15047 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

No genCC data.

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SETDB1 gene.

• not provided (23 variants)
• Inborn genetic diseases (8 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SETDB1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				9	2	11
missense			9	2	3	14
nonsense						0
start loss						0
frameshift			1		1	2
inframe indel						0
splice donor/acceptor (+/-2bp)			1			1
splice region				2		2
non coding				1		1
Total	0	0	11	12	6

Variants in SETDB1

This is a list of pathogenic ClinVar variants found in the SETDB1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
1-150929964-T-C			Likely benign (Feb 01, 2023)
1-150930021-A-G			Likely benign (Jul 02, 2018)
1-150939931-C-T			Likely benign (Dec 31, 2019)
1-150939954-A-C			Likely benign (Mar 01, 2024)
1-150939977-A-G			Likely benign (Mar 01, 2024)
1-150941367-A-C		not specified	Uncertain significance (Jan 04, 2022)
1-150942567-C-T			Likely benign (Apr 25, 2018)
1-150942666-C-G			Likely benign (Apr 16, 2018)
1-150942850-A-G			Uncertain significance (Aug 01, 2018)
1-150942901-A-G			Likely benign (Jan 19, 2018)
1-150942957-T-C		not specified	Uncertain significance (Jun 29, 2022)
1-150943990-C-G		not specified	Uncertain significance (Jul 26, 2021)
1-150944928-T-C			Likely benign (Apr 25, 2018)
1-150945146-G-GT			Benign (Mar 03, 2015)
1-150946983-A-G		not specified	Uncertain significance (Apr 13, 2022)
1-150947007-A-G		not specified	Uncertain significance (Apr 08, 2022)
1-150949193-C-T			Likely benign (Jan 31, 2018)
1-150949261-C-G			Benign (Jan 30, 2018)
1-150950463-C-T			Benign (Dec 31, 2019)
1-150950706-G-A			Uncertain significance (Mar 31, 2022)
1-150951098-G-C			Likely benign (Jul 27, 2018)
1-150951416-A-G			Likely benign (Aug 20, 2018)
1-150951422-C-G			Likely benign (Mar 30, 2018)
1-150960754-C-G		not specified	Uncertain significance (Jan 09, 2024)
1-150960883-G-C		not specified	Uncertain significance (Dec 22, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SETDB1	protein_coding	protein_coding	ENST00000271640	21	38475

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.00000446	125736	0	12	125748	0.0000477

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	4.01	434	741	0.586	0.0000424	8483
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000291	0.0000291
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.0000704	0.0000703
Middle Eastern	0.0000544	0.0000544
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

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}.
• Pathway: Lysine degradation - Homo sapiens (human);Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human);Histone Modifications;PKMTs methylate histone lysines;Chromatin modifying enzymes;Lysine metabolism;Noncanonical Wnt signaling pathway;Chromatin organization (Consensus)

Intolerance Scores

• loftool: 0.0153
• rvis_EVS: -1.46
• rvis_percentile_EVS: 3.81

Haploinsufficiency Scores

• pHI: 0.134
• hipred: Y
• hipred_score: 0.833
• ghis: 0.615

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 1.00

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Setdb1
• Phenotype: cellular phenotype; normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); embryo phenotype

Gene ontology

• Biological process: Ras protein signal transduction;response to vitamin;histone lysine methylation;response to ethanol;positive regulation of methylation-dependent chromatin silencing
• Cellular component: nucleus;nucleoplasm;chromosome;cytosol;plasma membrane;intracellular membrane-bounded organelle
• Molecular function: DNA binding;chromatin binding;protein binding;zinc ion binding;histone-lysine N-methyltransferase activity;promoter-specific chromatin binding