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    SETD2 SET domain containing 2, histone lysine methyltransferase [ Homo sapiens (human) ]

    Gene ID: 29072, updated on 2-Nov-2024

    Summary

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    Official Symbol
    SETD2provided by HGNC
    Official Full Name
    SET domain containing 2, histone lysine methyltransferaseprovided by HGNC
    Primary source
    HGNC:HGNC:18420
    See related
    Ensembl:ENSG00000181555 MIM:612778; AllianceGenome:HGNC:18420
    Gene type
    protein coding
    RefSeq status
    REVIEWED
    Organism
    Homo sapiens
    Lineage
    Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
    Also known as
    LLS; HYPB; SET2; HIF-1; HIP-1; KMT3A; MRD70; RAPAS; HBP231; HSPC069; p231HBP
    Summary
    Huntington's disease (HD), a neurodegenerative disorder characterized by loss of striatal neurons, is caused by an expansion of a polyglutamine tract in the HD protein huntingtin. This gene encodes a protein belonging to a class of huntingtin interacting proteins characterized by WW motifs. This protein is a histone methyltransferase that is specific for lysine-36 of histone H3, and methylation of this residue is associated with active chromatin. This protein also contains a novel transcriptional activation domain and has been found associated with hyperphosphorylated RNA polymerase II. [provided by RefSeq, Aug 2008]
    Expression
    Ubiquitous expression in bone marrow (RPKM 11.9), testis (RPKM 11.0) and 25 other tissues See more
    Orthologs
    mouse all
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    Genomic context

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    See SETD2 in Genome Data Viewer
    Location:
    3p21.31
    Exon count:
    25
    Annotation release Status Assembly Chr Location
    RS_2024_08 current GRCh38.p14 (GCF_000001405.40) 3 NC_000003.12 (47016436..47164840, complement)
    RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) 3 NC_060927.1 (47032799..47180480, complement)
    RS_2024_09 previous assembly GRCh37.p13 (GCF_000001405.25) 3 NC_000003.11 (47057926..47205603, complement)

    Chromosome 3 - NC_000003.12Genomic Context describing neighboring genes Neighboring gene coiled-coil domain containing 12 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr3:47021430-47022210 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr3:47022211-47022991 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr3:47026300-47027052 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 19806 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 14301 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 19807 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr3:47039103-47039996 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr3:47050749-47051546 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr3:47051547-47052343 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr3:47054299-47054798 Neighboring gene neurobeachin like 2 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 14303 Neighboring gene ReSE screen-validated silencer GRCh37_chr3:47082829-47083038 Neighboring gene neurotrophin receptor associated death domain, pseudogene Neighboring gene mitochondrial ribosomal protein L57 pseudogene 3 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr3:47108907-47109512 Neighboring gene NANOG hESC enhancer GRCh37_chr3:47125242-47125743 Neighboring gene uncharacterized LOC124906375 Neighboring gene OCT4-NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr3:47155200-47155707 Neighboring gene OCT4-NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr3:47155708-47156216 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 14304 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 14305 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 14306 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 14307 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 19809 Neighboring gene KIF9 antisense RNA 1 Neighboring gene MPRA-validated peak4632 silencer Neighboring gene H3K4me1 hESC enhancer GRCh37_chr3:47238926-47239426 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 19810 Neighboring gene OCT4-NANOG-H3K27ac hESC enhancer GRCh37_chr3:47301362-47302268 Neighboring gene small nucleolar RNA, C/D box 13 pseudogene 3 Neighboring gene small nucleolar RNA, C/D box 13J Neighboring gene kinesin family member 9 Neighboring gene CDK7 strongly-dependent group 2 enhancer GRCh37_chr3:47323613-47324812 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 19812 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 14308 Neighboring gene kelch like family member 18 Neighboring gene Sharpr-MPRA regulatory region 13740

    Genomic regions, transcripts, and products

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    Go to nucleotide: Graphics FASTA GenBank

    Expression

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    • Project title: HPA RNA-seq normal tissues HPA RNA-seq normal tissues
    • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
    • BioProject: PRJEB4337
    • Publication: PMID 24309898
    • Analysis date: Wed Apr 4 07:08:55 2018

    Bibliography

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    Related articles in PubMed

    1. Mutation pattern and genotype-phenotype correlations of SETD2 in neurodevelopmental disorders. Chen M, et al. Eur J Med Genet, 2021 May. PMID 33766796
    2. SETD2 related overgrowth syndrome: Presentation of four new patients and review of the literature. Marzin P, et al. Am J Med Genet C Semin Med Genet, 2019 Dec. PMID 31643139
    3. SETD2 Mutation in an Aggressive Optic Nerve Glioma. Campbell AA, et al. JAMA Ophthalmol, 2020 Jan 1. PMID 31697302
    4. Mutations in SETD2 cause a novel overgrowth condition. Luscan A, et al. J Med Genet, 2014 Aug. PMID 24852293
    5. SETD2 mutation in renal clear cell carcinoma suppress autophagy via regulation of ATG12. González-Rodríguez P, et al. Cell Death Dis, 2020 Jan 27. PMID 31988284, Free PMC Article

    See all (208) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. Regulation of SETD2 maintains immune regulatory function in macrophages to suppress airway allergy.
      Title: Regulation of SETD2 maintains immune regulatory function in macrophages to suppress airway allergy.
    2. Prognostic and therapeutic roles of SETD2 in cutaneous melanoma.
      Title: Prognostic and therapeutic roles of SETD2 in cutaneous melanoma.
    3. Methyltransferase Setd2 prevents T cell-mediated autoimmune diseases via phospholipid remodeling.
      Title: Methyltransferase Setd2 prevents T cell-mediated autoimmune diseases via phospholipid remodeling.
    4. Morphological characteristics of SETD2-mutated locally advanced clear cell renal cell carcinoma: Comparison with BAP1-mutated clear cell renal cell carcinoma.
      Title: Morphological characteristics of SETD2-mutated locally advanced clear cell renal cell carcinoma: Comparison with BAP1-mutated clear cell renal cell carcinoma.
    5. SETD2 mutations do not contribute to clonal fitness in response to chemotherapy in childhood B cell acute lymphoblastic leukemia.
      Title: SETD2 mutations do not contribute to clonal fitness in response to chemotherapy in childhood B cell acute lymphoblastic leukemia.
    6. SETD2 loss in renal epithelial cells drives epithelial-to-mesenchymal transition in a TGF-beta-independent manner.
      Title: SETD2 loss in renal epithelial cells drives epithelial-to-mesenchymal transition in a TGF-β-independent manner.
    7. Effects of SETD2 on telomere length and malignant transformation property of Met-5A after one-month crocidolite exposure.
      Title: Effects of SETD2 on telomere length and malignant transformation property of Met-5A after one-month crocidolite exposure.
    8. SETD2 deficiency promotes renal fibrosis through the TGF-beta/Smad signalling pathway in the absence of VHL.
      Title: SETD2 deficiency promotes renal fibrosis through the TGF-β/Smad signalling pathway in the absence of VHL.
    9. Loss of SETD2 aggravates colorectal cancer progression caused by SMAD4 deletion through the RAS/ERK signalling pathway.
      Title: Loss of SETD2 aggravates colorectal cancer progression caused by SMAD4 deletion through the RAS/ERK signalling pathway.
    10. Epigenotype-genotype-phenotype correlations in SETD1A and SETD2 chromatin disorders.
      Title: Epigenotype-genotype-phenotype correlations in SETD1A and SETD2 chromatin disorders.
    Submit: New GeneRIF Correction See all GeneRIFs (125)

    Phenotypes

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    Find tests for this gene in the NIH Genetic Testing Registry (GTR)

    Review eQTL and phenotype association data in this region using PheGenI

    Associated conditions

    Description Tests
    Intellectual developmental disorder, autosomal dominant 70
    MedGen: C5774271 OMIM: 620157 GeneReviews: SETD2 Neurodevelopmental Disorders
    		not available
    Luscan-Lumish syndrome
    MedGen: C4085873 OMIM: 616831 GeneReviews: SETD2 Neurodevelopmental Disorders
    		not available
    Rabin-Pappas syndrome
    MedGen: C5774269 OMIM: 620155 GeneReviews: SETD2 Neurodevelopmental Disorders
    		not available

    Copy number response

    Description
    Copy number response
    Haploinsufficency

    Sufficient evidence for dosage pathogenicity (Last evaluated 2022-03-08)

    ClinGen Genome Curation PagePubMed
    Triplosensitivity

    No evidence available (Last evaluated 2022-03-08)

    ClinGen Genome Curation Page

    EBI GWAS Catalog

    Description
    Discovery and refinement of loci associated with lipid levels.
    EBI GWAS Catalog

    Variation

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    See variants in ClinVar

    See studies and variants in dbVar

    See Variation Viewer (GRCh37.p13)

    See Variation Viewer (GRCh38)

    Genotypes

    Pathways from PubChem

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    Interactions

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    Products Interactant Other Gene Complex Source Pubs Description

    General gene information

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    Markers

    Homology

    Clone Names

    • FLJ16420, FLJ22472, FLJ23184, FLJ45883, FLJ46217, KIAA1732

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    enables alpha-tubulin binding IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    enables histone H3 methyltransferase activity TAS
    Traceable Author Statement
    more info
    		  
    enables histone H3K36 methyltransferase activity IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    enables histone H3K36 methyltransferase activity IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    enables histone H3K36 methyltransferase activity IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    enables histone H3K36 trimethyltransferase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables metal ion binding IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables protein binding IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    enables protein-lysine N-methyltransferase activity IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    Process Evidence Code Pubs
    involved_in angiogenesis IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in cell migration involved in vasculogenesis IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in coronary vasculature morphogenesis IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in defense response to virus IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in embryonic cranial skeleton morphogenesis IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in embryonic placenta morphogenesis IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in endodermal cell differentiation ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    involved_in forebrain development IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in mesoderm morphogenesis IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in microtubule cytoskeleton organization involved in mitosis IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in mismatch repair IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    involved_in morphogenesis of a branching structure IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in neural tube closure IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in nucleosome organization IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    involved_in peptidyl-lysine trimethylation IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in pericardium development IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in positive regulation of autophagy IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in positive regulation of interferon-alpha production IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in positive regulation of ossification IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in regulation of DNA-templated transcription IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in regulation of cytokinesis IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in regulation of double-strand break repair via homologous recombination IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in regulation of gene expression IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in regulation of mRNA export from nucleus IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    involved_in regulation of protein localization to chromatin IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in response to alkaloid IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in response to metal ion IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in response to organic cyclic compound IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in response to type I interferon IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in stem cell development IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in stem cell differentiation ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    involved_in transcription elongation by RNA polymerase II IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    Component Evidence Code Pubs
    is_active_in chromosome IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    located_in chromosome ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    is_active_in cytoplasm IC
    Inferred by Curator
    more info
    		 PubMed 
    located_in nucleoplasm TAS
    Traceable Author Statement
    more info
    		  
    is_active_in nucleus IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    located_in nucleus ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  

    General protein information

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    Preferred Names
    histone-lysine N-methyltransferase SETD2
    Names
    huntingtin interacting protein 1
    huntingtin yeast partner B
    huntingtin-interacting protein B
    lysine N-methyltransferase 3A
    protein-lysine N-methyltransferase SETD2
    NP_001336299.1
    NP_054878.5
    XP_024309255.1
    XP_024309256.1
    XP_024309257.1
    XP_047304001.1

    NCBI Reference Sequences (RefSeq)

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    NEW Try the new Transcript table

    RefSeqs maintained independently of Annotated Genomes

    These reference sequences exist independently of genome builds. Explain

    These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

    Genomic

    1. NG_032091.1 RefSeqGene

      Range
      5001..152570
      Download
      GenBank, FASTA, Sequence Viewer (Graphics), LRG_775

    mRNA and Protein(s)

    1. NM_001349370.3 → NP_001336299.1  histone-lysine N-methyltransferase SETD2 isoform 2

      Status: REVIEWED

      Description
      Transcript Variant: This variant (2) differs in the 5' UTR and coding sequence compared to variant 1. The resulting isoform (2) is shorter at the N-terminus compared to isoform 1.
      Source sequence(s)
      AC094020, AC127430
      Consensus CDS
      CCDS93261.1
      UniProtKB/TrEMBL
      A0A1W2PPX9, A0A8I5KV15
      Related
      ENSP00000491413.2, ENST00000638947.2
      Conserved Domains (6) summary
      pfam05279
      Location:1896 → 2079
      Asp-B-Hydro_N; Aspartyl beta-hydroxylase N-terminal region
      smart00570
      Location:1451 → 1505
      AWS; associated with SET domains
      smart00317
      Location:1506 → 1629
      SET; SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain
      smart00508
      Location:1630 → 1646
      PostSET; Cysteine-rich motif following a subset of SET domains
      pfam00397
      Location:2347 → 2376
      WW; WW domain
      pfam08236
      Location:2425 → 2512
      SRI; SRI (Set2 Rpb1 interacting) domain

    2. NM_014159.7 → NP_054878.5  histone-lysine N-methyltransferase SETD2 isoform 1

      See identical proteins and their annotated locations for NP_054878.5

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) encodes the longer isoform (1).
      Source sequence(s)
      AC094020, AC127430, AI671342, AK127782, AY576987, BC117162, BX649110, DA800082
      Consensus CDS
      CCDS2749.2
      UniProtKB/Swiss-Prot
      O75397, O75405, Q17RW8, Q5BKS9, Q5QGN2, Q69YI5, Q6IN64, Q6ZN53, Q6ZS25, Q8N3R0, Q8TCN0, Q9BYW2, Q9C0D1, Q9H696, Q9NZW9
      UniProtKB/TrEMBL
      A0A8I5KV15
      Related
      ENSP00000386759.3, ENST00000409792.4
      Conserved Domains (6) summary
      pfam05279
      Location:1940 → 2123
      Asp-B-Hydro_N; Aspartyl beta-hydroxylase N-terminal region
      smart00570
      Location:1495 → 1549
      AWS; associated with SET domains
      smart00317
      Location:1550 → 1673
      SET; SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain
      smart00508
      Location:1674 → 1690
      PostSET; Cysteine-rich motif following a subset of SET domains
      pfam00397
      Location:2391 → 2420
      WW; WW domain
      pfam08236
      Location:2469 → 2548
      SRI; SRI (Set2 Rpb1 interacting) domain

    RNA

    1. NR_146158.3 RNA Sequence

      Status: REVIEWED

      Description
      Transcript Variant: This variant (3) contains an alternate exon compared to variant 1. This variant is represented as non-coding because the use of the 5'-most expected translational start codon renders the transcript a candidate for nonsense-mediated mRNA decay (NMD).
      Source sequence(s)
      AC094020, AC127430
      Related
      ENST00000431180.5

    RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2024_08

    The following sections contain reference sequences that belong to a specific genome build. Explain

    Reference GRCh38.p14 Primary Assembly

    Genomic

    1. NC_000003.12 Reference GRCh38.p14 Primary Assembly

      Range
      47016436..47164840 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_024453487.2 → XP_024309255.1  histone-lysine N-methyltransferase SETD2 isoform X3

      UniProtKB/TrEMBL
      A0A8I5KV15
      Related
      ENSP00000509568.1, ENST00000685005.1
      Conserved Domains (6) summary
      pfam05279
      Location:1851 → 2034
      Asp-B-Hydro_N; Aspartyl beta-hydroxylase N-terminal region
      smart00570
      Location:1451 → 1505
      AWS; associated with SET domains
      smart00317
      Location:1506 → 1629
      SET; SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain
      smart00508
      Location:1630 → 1646
      PostSET; Cysteine-rich motif following a subset of SET domains
      pfam00397
      Location:2302 → 2331
      WW; WW domain
      pfam08236
      Location:2380 → 2467
      SRI; SRI (Set2 Rpb1 interacting) domain

    2. XM_047448045.1 → XP_047304001.1  histone-lysine N-methyltransferase SETD2 isoform X1

      UniProtKB/TrEMBL
      A0A1W2PPX9

    3. XM_024453488.2 → XP_024309256.1  histone-lysine N-methyltransferase SETD2 isoform X2

      UniProtKB/TrEMBL
      A0A8I5KV15
      Conserved Domains (5) summary
      pfam05279
      Location:1796 → 1979
      Asp-B-Hydro_N; Aspartyl beta-hydroxylase N-terminal region
      smart00570
      Location:1451 → 1505
      AWS; associated with SET domains
      smart00508
      Location:1530 → 1546
      PostSET; Cysteine-rich motif following a subset of SET domains
      pfam00397
      Location:2247 → 2276
      WW; WW domain
      pfam08236
      Location:2325 → 2412
      SRI; SRI (Set2 Rpb1 interacting) domain

    4. XM_024453489.1 → XP_024309257.1  histone-lysine N-methyltransferase SETD2 isoform X4

      UniProtKB/TrEMBL
      H7BXT4
      Conserved Domains (2) summary
      smart00570
      Location:1451 → 1505
      AWS; associated with SET domains
      smart00317
      Location:1506 → 1595
      SET; SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain

    RNA

    1. XR_007095670.1 RNA Sequence

    2. XR_002959514.2 RNA Sequence

    3. XR_007095673.1 RNA Sequence

    4. XR_007095672.1 RNA Sequence

    5. XR_007095671.1 RNA Sequence

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060927.1 Alternate T2T-CHM13v2.0

      Range
      47032799..47180480 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    Suppressed Reference Sequence(s)

    The following Reference Sequences have been suppressed. Explain

    1. NM_012271.1: Suppressed sequence

      Description
      NM_012271.1: This RefSeq was permanently suppressed because it is a nonsense-mediated mRNA decay (NMD) candidate.
    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    Q9BYW2.3 GenPept UniProtKB/Swiss-Prot:Q9BYW2

    Gene LinkOut

    The following LinkOut resources are supplied by external providers. These providers are responsible for maintaining the links.

    Chemical Information
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