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    RNF38 ring finger protein 38 [ Homo sapiens (human) ]

    Gene ID: 152006, updated on 27-Nov-2024

    Summary

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    Official Symbol
    RNF38provided by HGNC
    Official Full Name
    ring finger protein 38provided by HGNC
    Primary source
    HGNC:HGNC:18052
    See related
    Ensembl:ENSG00000137075 MIM:612488; AllianceGenome:HGNC:18052
    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
    Summary
    This gene encodes a protein with a coiled-coil motif and a RING-H2 motif (C3H2C2) at its carboxy-terminus. The RING motif is a zinc-binding domain found in a large set of proteins playing roles in diverse cellular processes including oncogenesis, development, signal transduction, and apoptosis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]
    Expression
    Ubiquitous expression in testis (RPKM 25.8), ovary (RPKM 14.9) and 25 other tissues See more
    Orthologs
    mouse all
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    Genomic context

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    See RNF38 in Genome Data Viewer
    Location:
    9p13.2
    Exon count:
    22
    Annotation release Status Assembly Chr Location
    RS_2024_08 current GRCh38.p14 (GCF_000001405.40) 9 NC_000009.12 (36336400..36487669, complement)
    RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) 9 NC_060933.1 (36358438..36510372, complement)
    RS_2024_09 previous assembly GRCh37.p13 (GCF_000001405.25) 9 NC_000009.11 (36336397..36401203, complement)

    Chromosome 9 - NC_000009.12Genomic Context describing neighboring genes Neighboring gene uncharacterized LOC124902150 Neighboring gene uncharacterized LOC102724322 Neighboring gene glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase Neighboring gene RNA, U4 small nuclear 53, pseudogene Neighboring gene high mobility group box 3 pseudogene 24 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr9:36391761-36392261 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 28350 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 19892 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 19893 Neighboring gene uncharacterized LOC124902152 Neighboring gene NANOG-H3K27ac hESC enhancer GRCh37_chr9:36415685-36416307 Neighboring gene mitochondrial ribosomal protein S21 pseudogene 4 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 28351 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 28352 Neighboring gene ReSE screen-validated silencer GRCh37_chr9:36482565-36482744 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 19894 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 19895 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 28353 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 28354 Neighboring gene H3K27ac hESC enhancer GRCh37_chr9:36558262-36558872 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr9:36571611-36572110 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 19896 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr9:36584821-36585797 Neighboring gene ReSE screen-validated silencer GRCh37_chr9:36596422-36596589 Neighboring gene maternal embryonic leucine zipper kinase Neighboring gene ATAC-STARR-seq lymphoblastoid active region 28355 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr9:36725931-36726432 Neighboring gene MED14-independent group 3 enhancer GRCh37_chr9:36738402-36739601 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 19897 Neighboring gene ReSE screen-validated silencer GRCh37_chr9:36756569-36756775 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr9:36764310-36764828 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr9:36764829-36765347 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 28356 Neighboring gene uncharacterized LOC105376030 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 19898 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr9:36820286-36820786 Neighboring gene microRNA 4475

    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
    • 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. Cloning and characterization of a novel human gene RNF38 encoding a conserved putative protein with a RING finger domain. Eisenberg I, et al. Biochem Biophys Res Commun, 2002 Jun 28. PMID 12074600
    2. Hsa_circ_0097009 regulates proliferation, apoptosis, migration and invasion of hepatocellular carcinoma cells via miR-568/RNF38 axis. Wu Z, et al. Bratisl Lek Listy, 2023. PMID 36598315
    3. RNF38 inhibits osteosarcoma cell proliferation by binding to CRY1. Zhou J, et al. Biochem Cell Biol, 2021 Oct. PMID 34460347
    4. RING finger protein 38 induces gastric cancer cell growth by decreasing the stability of the protein tyrosine phosphatase SHP-1. Zhang J, et al. FEBS Lett, 2018 Sep. PMID 30112836
    5. Inhibiting microRNA-301b suppresses cell growth and targets RNF38 in cervical carcinoma. Guo WL, et al. Kaohsiung J Med Sci, 2020 Nov. PMID 32643846

    See all (39) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. Hsa_circ_0097009 regulates proliferation, apoptosis, migration and invasion of hepatocellular carcinoma cells via miR-568/RNF38 axis.
      Title: Hsa_circ_0097009 regulates proliferation, apoptosis, migration and invasion of hepatocellular carcinoma cells via miR-568/RNF38 axis.
    2. RNF38 suppress growth and metastasis via ubiquitination of ACTN4 in nasopharyngeal carcinoma.
      Title: RNF38 suppress growth and metastasis via ubiquitination of ACTN4 in nasopharyngeal carcinoma.
    3. RNF38 inhibits osteosarcoma cell proliferation by binding to CRY1.
      Title: RNF38 inhibits osteosarcoma cell proliferation by binding to CRY1.
    4. Inhibiting microRNA-301b suppresses cell growth and targets RNF38 in cervical carcinoma.
      Title: Inhibiting microRNA-301b suppresses cell growth and targets RNF38 in cervical carcinoma.
    5. Long non-coding RNA SNHG5 promotes human hepatocellular carcinoma progression by regulating miR-363-3p/RNF38 axis.
      Title: Long non-coding RNA SNHG5 promotes human hepatocellular carcinoma progression by regulating miR-363-3p/RNF38 axis.
    6. Data show that E3 ubiquitin-protein ligase RNF38 (RNF38) interacts with the nonreceptor tyrosine phosphatase SH2-containing protein tyrosine phosphatase 1 (SHP-1) and induces the polyubiquitination of SHP-1, which leads to destabilization of SHP-1.
      Title: RING finger protein 38 induces gastric cancer cell growth by decreasing the stability of the protein tyrosine phosphatase SHP-1.
    7. AHNAK interference restored the hepatocellular carcinoma (HCC) cell invasion and metastasis deprived by RNF38 downregulation. Clinically, elevated RNF38 and transforming growth factor beta receptor 1 (TGFBR1) expression was related to short overall survival (OS) and high cumulative recurrence rates in HCC patients.
      Title: Overexpression of RNF38 facilitates TGF-β signaling by Ubiquitinating and degrading AHNAK in hepatocellular carcinoma.
    8. identified RNF38 as a novel E3 ligase that modifies RUNX1 function without inducing its degradation
      Title: The ubiquitin ligase RNF38 promotes RUNX1 ubiquitination and enhances RUNX1-mediated suppression of erythroid transcription program.
    9. These results suggest RNF38 is an E3 ubiquitin ligase that may play a role in regulating p53.
      Title: RNF38 encodes a nuclear ubiquitin protein ligase that modifies p53.
    10. Cloning and characterization of the RNF38 gene
      Title: Cloning and characterization of a novel human gene RNF38 encoding a conserved putative protein with a RING finger domain.
    Submit: New GeneRIF Correction

    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

    Variation

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    See variants in ClinVar

    See studies and variants in dbVar

    See Variation Viewer (GRCh37.p13)

    See Variation Viewer (GRCh38)

    Interactions

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    Products Interactant Other Gene Complex Source Pubs Description

    General gene information

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    Markers

    Homology

    Clone Names

    • FLJ21343

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    enables metal ion binding IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables protein binding IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    enables ubiquitin protein ligase activity IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    enables ubiquitin protein ligase activity IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    Process Evidence Code Pubs
    involved_in male gonad development IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in protein ubiquitination IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in protein ubiquitination IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in protein ubiquitination IEA
    Inferred from Electronic Annotation
    more info
    		  
    Component Evidence Code Pubs
    located_in nucleoplasm IDA
    Inferred from Direct Assay
    more info
    		  
    located_in nucleus IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    located_in sperm flagellum IEA
    Inferred from Electronic Annotation
    more info
    		  

    General protein information

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    Preferred Names
    E3 ubiquitin-protein ligase RNF38
    Names
    RING-type E3 ubiquitin transferase RNF38
    NP_073618.3
    NP_919309.1
    NP_919310.1
    NP_919311.1
    NP_919313.1
    XP_005251423.1
    XP_005251424.1
    XP_006716784.1
    XP_011516014.1
    XP_011516015.1
    XP_016869783.1
    XP_016869785.1
    XP_016869786.1
    XP_047278750.1
    XP_047278751.1
    XP_047278752.1
    XP_047278753.1
    XP_047278754.1
    XP_047278755.1
    XP_047278756.1
    XP_047278757.1
    XP_047278758.1
    XP_047278759.1
    XP_047278760.1
    XP_047278761.1
    XP_047278762.1
    XP_054217976.1
    XP_054217977.1
    XP_054217978.1
    XP_054217979.1
    XP_054217980.1
    XP_054217981.1
    XP_054217982.1
    XP_054217983.1
    XP_054217984.1
    XP_054217985.1
    XP_054217986.1
    XP_054217987.1
    XP_054217988.1
    XP_054217989.1
    XP_054217990.1
    XP_054217991.1
    XP_054217992.1
    XP_054217993.1
    XP_054217994.1
    XP_054217995.1

    NCBI Reference Sequences (RefSeq)

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    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.

    mRNA and Protein(s)

    1. NM_022781.5 → NP_073618.3  E3 ubiquitin-protein ligase RNF38 isoform 1

      See identical proteins and their annotated locations for NP_073618.3

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) encodes the longest isoform (1).
      Source sequence(s)
      AF394047, AL120640, AL136817, AL161792, BC033786
      Consensus CDS
      CCDS6603.1
      UniProtKB/Swiss-Prot
      A6PVP9, B1AM81, B1AM82, B3KSG4, E7EVL3, Q7LB33, Q8N0Y0, Q9H0F5, Q9H748
      Related
      ENSP00000259605.6, ENST00000259605.11
      Conserved Domains (1) summary
      cd16472
      Location:460 → 504
      RING-H2_RNF38_like; RING finger, H2 subclass, found in RING finger proteins RNF38, RNF44, and similar proteins

    2. NM_194328.3 → NP_919309.1  E3 ubiquitin-protein ligase RNF38 isoform 2

      See identical proteins and their annotated locations for NP_919309.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (2) has an alternate 5' terminal exon compared to variant 1. This difference causes translation initiation at a downstream AUG and an isoform (2) with a shorter N-terminus compared to isoform 1. Variants 2, 5 and 6 encode the same isoform.
      Source sequence(s)
      AF394047, AL161792, AL354935, BG722531, BI459742
      UniProtKB/Swiss-Prot
      Q9H0F5
      Related
      ENSP00000349566.3, ENST00000357058.7
      Conserved Domains (1) summary
      cd16472
      Location:377 → 421
      RING-H2_RNF38_like; RING finger, H2 subclass, found in RING finger proteins RNF38, RNF44, and similar proteins

    3. NM_194329.3 → NP_919310.1  E3 ubiquitin-protein ligase RNF38 isoform 3

      See identical proteins and their annotated locations for NP_919310.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (3) lacks an alternate in-frame exon, compared to variant 1, resulting in a shorter protein (isoform 3), compared to isoform 1.
      Source sequence(s)
      AF394047, AL120640, AL161792, BC033786
      Consensus CDS
      CCDS6604.1
      UniProtKB/Swiss-Prot
      Q9H0F5
      Related
      ENSP00000335239.5, ENST00000353739.8
      Conserved Domains (1) summary
      cd16472
      Location:410 → 454
      RING-H2_RNF38_like; RING finger, H2 subclass, found in RING finger proteins RNF38, RNF44, and similar proteins

    4. NM_194330.3 → NP_919311.1  E3 ubiquitin-protein ligase RNF38 isoform 2

      See identical proteins and their annotated locations for NP_919311.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (5) has an alternate 5' terminal exon compared to variant 1. This difference causes translation initiation at a downstream AUG and an isoform (2) with a shorter N-terminus compared to isoform 1. Variants 2, 5 and 6 encode the same isoform.
      Source sequence(s)
      AF394047, AL161792, AL354935, BC033786, BI520161, DA483270
      UniProtKB/Swiss-Prot
      Q9H0F5
      Related
      ENSP00000367117.2, ENST00000377885.6
      Conserved Domains (1) summary
      cd16472
      Location:377 → 421
      RING-H2_RNF38_like; RING finger, H2 subclass, found in RING finger proteins RNF38, RNF44, and similar proteins

    5. NM_194332.3 → NP_919313.1  E3 ubiquitin-protein ligase RNF38 isoform 2

      See identical proteins and their annotated locations for NP_919313.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (6) has an alternate 5' terminal exon and lacks an exon compared to variant 1. These differences cause translation initiation at a downstream AUG and an isoform (2) with a shorter N-terminus compared to isoform 1. Variants 2, 5 and 6 encode the same isoform.
      Source sequence(s)
      AF394047, AL161792, AL354935, BG722531, BI459742, DA189510
      UniProtKB/Swiss-Prot
      Q9H0F5
      Related
      ENSP00000343947.4, ENST00000350199.8
      Conserved Domains (1) summary
      cd16472
      Location:377 → 421
      RING-H2_RNF38_like; RING finger, H2 subclass, found in RING finger proteins RNF38, RNF44, and similar proteins

    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_000009.12 Reference GRCh38.p14 Primary Assembly

      Range
      36336400..36487669 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_047422796.1 → XP_047278752.1  E3 ubiquitin-protein ligase RNF38 isoform X3

    2. XM_047422795.1 → XP_047278751.1  E3 ubiquitin-protein ligase RNF38 isoform X2

    3. XM_047422794.1 → XP_047278750.1  E3 ubiquitin-protein ligase RNF38 isoform X1

    4. XM_017014296.2 → XP_016869785.1  E3 ubiquitin-protein ligase RNF38 isoform X7

      Conserved Domains (1) summary
      cd16472
      Location:347 → 391
      RING-H2_RNF38_like; RING finger, H2 subclass, found in RING finger proteins RNF38, RNF44, and similar proteins

    5. XM_011517712.3 → XP_011516014.1  E3 ubiquitin-protein ligase RNF38 isoform X6

      See identical proteins and their annotated locations for XP_011516014.1

      UniProtKB/Swiss-Prot
      Q9H0F5
      Conserved Domains (1) summary
      cd16472
      Location:377 → 421
      RING-H2_RNF38_like; RING finger, H2 subclass, found in RING finger proteins RNF38, RNF44, and similar proteins

    6. XM_017014297.2 → XP_016869786.1  E3 ubiquitin-protein ligase RNF38 isoform X7

      Conserved Domains (1) summary
      cd16472
      Location:347 → 391
      RING-H2_RNF38_like; RING finger, H2 subclass, found in RING finger proteins RNF38, RNF44, and similar proteins

    7. XM_047422803.1 → XP_047278759.1  E3 ubiquitin-protein ligase RNF38 isoform X6

    8. XM_017014294.2 → XP_016869783.1  E3 ubiquitin-protein ligase RNF38 isoform X5

    9. XM_047422802.1 → XP_047278758.1  E3 ubiquitin-protein ligase RNF38 isoform X6

    10. XM_047422805.1 → XP_047278761.1  E3 ubiquitin-protein ligase RNF38 isoform X6

    11. XM_006716721.4 → XP_006716784.1  E3 ubiquitin-protein ligase RNF38 isoform X6

      See identical proteins and their annotated locations for XP_006716784.1

      UniProtKB/Swiss-Prot
      Q9H0F5
      Conserved Domains (1) summary
      cd16472
      Location:377 → 421
      RING-H2_RNF38_like; RING finger, H2 subclass, found in RING finger proteins RNF38, RNF44, and similar proteins

    12. XM_005251367.4 → XP_005251424.1  E3 ubiquitin-protein ligase RNF38 isoform X6

      See identical proteins and their annotated locations for XP_005251424.1

      UniProtKB/Swiss-Prot
      Q9H0F5
      Conserved Domains (1) summary
      cd16472
      Location:377 → 421
      RING-H2_RNF38_like; RING finger, H2 subclass, found in RING finger proteins RNF38, RNF44, and similar proteins

    13. XM_005251366.4 → XP_005251423.1  E3 ubiquitin-protein ligase RNF38 isoform X6

      See identical proteins and their annotated locations for XP_005251423.1

      UniProtKB/Swiss-Prot
      Q9H0F5
      Conserved Domains (1) summary
      cd16472
      Location:377 → 421
      RING-H2_RNF38_like; RING finger, H2 subclass, found in RING finger proteins RNF38, RNF44, and similar proteins

    14. XM_011517713.3 → XP_011516015.1  E3 ubiquitin-protein ligase RNF38 isoform X6

      See identical proteins and their annotated locations for XP_011516015.1

      UniProtKB/Swiss-Prot
      Q9H0F5
      Conserved Domains (1) summary
      cd16472
      Location:377 → 421
      RING-H2_RNF38_like; RING finger, H2 subclass, found in RING finger proteins RNF38, RNF44, and similar proteins

    15. XM_047422801.1 → XP_047278757.1  E3 ubiquitin-protein ligase RNF38 isoform X6

    16. XM_047422804.1 → XP_047278760.1  E3 ubiquitin-protein ligase RNF38 isoform X6

    17. XM_047422800.1 → XP_047278756.1  E3 ubiquitin-protein ligase RNF38 isoform X6

      Related
      ENSP00000483536.1, ENST00000611646.4

    18. XM_047422797.1 → XP_047278753.1  E3 ubiquitin-protein ligase RNF38 isoform X4

    19. XM_047422799.1 → XP_047278755.1  E3 ubiquitin-protein ligase RNF38 isoform X6

    20. XM_047422798.1 → XP_047278754.1  E3 ubiquitin-protein ligase RNF38 isoform X6

    21. XM_047422806.1 → XP_047278762.1  E3 ubiquitin-protein ligase RNF38 isoform X6

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060933.1 Alternate T2T-CHM13v2.0

      Range
      36358438..36510372 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_054362003.1 → XP_054217978.1  E3 ubiquitin-protein ligase RNF38 isoform X3

    2. XM_054362001.1 → XP_054217976.1  E3 ubiquitin-protein ligase RNF38 isoform X1

    3. XM_054362002.1 → XP_054217977.1  E3 ubiquitin-protein ligase RNF38 isoform X2

    4. XM_054362018.1 → XP_054217993.1  E3 ubiquitin-protein ligase RNF38 isoform X7

    5. XM_054362019.1 → XP_054217994.1  E3 ubiquitin-protein ligase RNF38 isoform X6

    6. XM_054362017.1 → XP_054217992.1  E3 ubiquitin-protein ligase RNF38 isoform X7

    7. XM_054362014.1 → XP_054217989.1  E3 ubiquitin-protein ligase RNF38 isoform X6

    8. XM_054362005.1 → XP_054217980.1  E3 ubiquitin-protein ligase RNF38 isoform X5

    9. XM_054362013.1 → XP_054217988.1  E3 ubiquitin-protein ligase RNF38 isoform X6

    10. XM_054362015.1 → XP_054217990.1  E3 ubiquitin-protein ligase RNF38 isoform X6

    11. XM_054362009.1 → XP_054217984.1  E3 ubiquitin-protein ligase RNF38 isoform X6

    12. XM_054362007.1 → XP_054217982.1  E3 ubiquitin-protein ligase RNF38 isoform X6

    13. XM_054362008.1 → XP_054217983.1  E3 ubiquitin-protein ligase RNF38 isoform X6

    14. XM_054362006.1 → XP_054217981.1  E3 ubiquitin-protein ligase RNF38 isoform X6

    15. XM_054362016.1 → XP_054217991.1  E3 ubiquitin-protein ligase RNF38 isoform X6

    16. XM_054362011.1 → XP_054217986.1  E3 ubiquitin-protein ligase RNF38 isoform X6

    17. XM_054362004.1 → XP_054217979.1  E3 ubiquitin-protein ligase RNF38 isoform X4

    18. XM_054362012.1 → XP_054217987.1  E3 ubiquitin-protein ligase RNF38 isoform X6

    19. XM_054362010.1 → XP_054217985.1  E3 ubiquitin-protein ligase RNF38 isoform X6

    20. XM_054362020.1 → XP_054217995.1  E3 ubiquitin-protein ligase RNF38 isoform X6

    Suppressed Reference Sequence(s)

    The following Reference Sequences have been suppressed. Explain

    1. NM_194331.1: Suppressed sequence

      Description
      NM_194331.1: This RefSeq was permanently suppressed because currently there is insufficient support for the transcript and the protein.
    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    Q9H0F5.4 GenPept UniProtKB/Swiss-Prot:Q9H0F5

    Gene LinkOut

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

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