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    SMPD4 sphingomyelin phosphodiesterase 4 [ Homo sapiens (human) ]

    Gene ID: 55627, updated on 10-Dec-2024

    Summary

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    Official Symbol
    SMPD4provided by HGNC
    Official Full Name
    sphingomyelin phosphodiesterase 4provided by HGNC
    Primary source
    HGNC:HGNC:32949
    See related
    Ensembl:ENSG00000136699 MIM:610457; AllianceGenome:HGNC:32949
    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
    SKNY; NET13; NEDMABA; NEDMEBA; NSMASE3; NSMASE-3
    Summary
    The protein encoded by this gene is a sphingomyelinase that catalyzes the hydrolysis of membrane sphingomyelin to form phosphorylcholine and ceramide. This gene is activated by DNA damage, cellular stress, and tumor necrosis factor, but it is downregulated by wild-type p53. The encoded protein localizes to the endoplasmic reticulum and Golgi network. [provided by RefSeq, Mar 2017]
    Expression
    Ubiquitous expression in bone marrow (RPKM 16.4), testis (RPKM 14.6) and 25 other tissues See more
    Orthologs
    mouse all
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    Genomic context

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    See SMPD4 in Genome Data Viewer
    Location:
    2q21.1
    Exon count:
    21
    Annotation release Status Assembly Chr Location
    RS_2024_08 current GRCh38.p14 (GCF_000001405.40) 2 NC_000002.12 (130151392..130181757, complement)
    RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) 2 NC_060926.1 (130585291..130615727, complement)
    RS_2024_09 previous assembly GRCh37.p13 (GCF_000001405.25) 2 NC_000002.11 (130908965..130939330, complement)

    Chromosome 2 - NC_000002.12Genomic Context describing neighboring genes Neighboring gene POTE ankyrin domain family member F Neighboring gene RNA, U6 small nuclear 1049, pseudogene Neighboring gene POTEF antisense RNA 1 Neighboring gene H3K27ac hESC enhancer GRCh37_chr2:130886707-130887281 Neighboring gene mediator complex subunit 15 pseudogene 9 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 16521 Neighboring gene coiled-coil domain containing 74B Neighboring gene ATAC-STARR-seq lymphoblastoid active region 16523 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr2:130917957-130918586 Neighboring gene ReSE screen-validated silencer GRCh37_chr2:130921824-130922007 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr2:130938087-130938883 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 11953 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 11954 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr2:130940784-130941520 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr2:130941521-130942257 Neighboring gene mitotic spindle organizing protein 2B Neighboring gene tubulin alpha 3e Neighboring gene ras homolog family member Q pseudogene 3

    Genomic regions, transcripts, and products

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    Go to nucleotide: Graphics FASTA GenBank

    Expression

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    • Project title: Tissue-specific circular RNA induction during human fetal development
    • Description: 35 human fetal samples from 6 tissues (3 - 7 replicates per tissue) collected between 10 and 20 weeks gestational time were sequenced using Illumina TruSeq Stranded Total RNA
    • BioProject: PRJNA270632
    • Publication: PMID 26076956
    • Analysis date: Mon Apr 2 22:54:59 2018

    Bibliography

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    Related articles in PubMed

    1. Proximity Ligation Mapping of Microcephaly Associated SMPD4 Shows Association with Components of the Nuclear Pore Membrane. Piët ACA, et al. Cells, 2022 Feb 15. PMID 35203325, Free PMC Article
    2. Two novel cases of biallelic SMPD4 variants with brain structural abnormalities. Aoki S, et al. Neurogenetics, 2024 Jan. PMID 37882972
    3. Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis. Magini P, et al. Am J Hum Genet, 2019 Oct 3. PMID 31495489, Free PMC Article
    4. Neutral sphingomyelinase-3 is a DNA damage and nongenotoxic stress-regulated gene that is deregulated in human malignancies. Corcoran CA, et al. Mol Cancer Res, 2008 May. PMID 18505924, Free PMC Article
    5. Neutral sphingomyelinase-3 mediates TNF-stimulated oxidant activity in skeletal muscle. Moylan JS, et al. Redox Biol, 2014. PMID 25180167, Free PMC Article

    See all (81) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. Two novel cases of biallelic SMPD4 variants with brain structural abnormalities.
      Title: Two novel cases of biallelic SMPD4 variants with brain structural abnormalities.
    2. Proximity Ligation Mapping of Microcephaly Associated SMPD4 Shows Association with Components of the Nuclear Pore Membrane.
      Title: Proximity Ligation Mapping of Microcephaly Associated SMPD4 Shows Association with Components of the Nuclear Pore Membrane.
    3. data show that SMPD4 links homeostasis of membrane sphingolipids to cell fate by regulating the cross-talk between the endoplasmic reticulum and the outer nuclear envelope, while its loss reveals a pathogenic mechanism in microcephaly
      Title: Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis.
    4. Observational study of gene-disease association, gene-environment interaction, and pharmacogenomic / toxicogenomic. (HuGE Navigator)
      Title: Variation at the NFATC2 locus increases the risk of thiazolidinedione-induced edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) study.
    5. Observational study of gene-disease association. (HuGE Navigator)
      Title: Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.
    6. Data show DA remarkably increased the NSMase2 message and protein, whereas little change in NSMase1 and NSMase3 mRNAs.
      Title: Transcriptional regulation of neutral sphingomyelinase 2 gene expression of a human breast cancer cell line, MCF-7, induced by the anti-cancer drug, daunorubicin.
    7. nSMase3 is an important molecule that is linked to tumorigenesis and cellular stress response
      Title: Neutral sphingomyelinase-3 is a DNA damage and nongenotoxic stress-regulated gene that is deregulated in human malignancies.
    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

    Associated conditions

    Description Tests
    Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies
    MedGen: C5231431 OMIM: 618622 GeneReviews: Not available
    		Compare labs

    Variation

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    See variants in ClinVar

    See studies and variants in dbVar

    See Variation Viewer (GRCh37.p13)

    See Variation Viewer (GRCh38)

    HIV-1 interactions

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    Protein interactions

    Protein Gene Interaction Pubs
    Envelope surface glycoprotein gp120 env HIV-1 gp120 binding to CXCR4 induces NADPH oxidase-mediated production of superoxide radicals in neurons, which is involved in the activation of neutral sphingomyelinase PubMed
    env In human primary neurons, HIV-1 gp120 induces the activation of sphingomyelinases (primarily neutral sphingomyelinase); antisense knockdown of neutral sphingomyelinase markedly inhibits gp120-mediated apoptosis and cell death of primary neurons PubMed

    Go to the HIV-1, Human Interaction Database

    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

    • FLJ20297, FLJ20756, KIAA1418

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    enables metal ion binding IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables sphingomyelin phosphodiesterase D activity IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    enables sphingomyelin phosphodiesterase D activity IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    enables sphingomyelin phosphodiesterase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    Process Evidence Code Pubs
    involved_in cellular response to tumor necrosis factor IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in ceramide biosynthetic process IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in ceramide biosynthetic process IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in endoplasmic reticulum organization IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    involved_in glycerophospholipid catabolic process IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in glycerophospholipid catabolic process IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in sphingomyelin catabolic process IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in sphingomyelin catabolic process IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    Component Evidence Code Pubs
    located_in Golgi apparatus IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    located_in Golgi membrane IEA
    Inferred from Electronic Annotation
    more info
    		  
    located_in endoplasmic reticulum IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    located_in endoplasmic reticulum membrane TAS
    Traceable Author Statement
    more info
    		  
    located_in nuclear envelope ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    located_in nuclear outer membrane IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    located_in sarcolemma ISS
    Inferred from Sequence or Structural Similarity
    more info
    		  
    located_in trans-Golgi network IDA
    Inferred from Direct Assay
    more info
    		 PubMed 

    General protein information

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    Preferred Names
    sphingomyelin phosphodiesterase 4
    Names
    neutral sphingomyelinase 3
    neutral sphingomyelinase III
    sphingomyelin phosphodiesterase 4, neutral membrane (neutral sphingomyelinase-3)
    NP_001164554.1
    NP_060221.2
    NP_060421.3
    XP_011509745.1
    XP_011509746.1
    XP_024308746.1
    XP_047300894.1
    XP_054188850.1
    XP_054188851.1
    XP_054188852.1
    XP_054188853.1
    XP_054188854.1
    XP_054188855.1
    XP_054188856.1
    XP_054188857.1
    XP_054188858.1
    XP_054188859.1
    XP_054198841.1
    XP_054198842.1
    XP_054198843.1
    XP_054198844.1
    XP_054198845.1
    XP_054198846.1
    XP_054198847.1
    XP_054198848.1
    XP_054198849.1
    XP_054198850.1

    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.

    Genomic

    1. NG_053070.1 RefSeqGene

      Range
      6149..36343
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. NM_001171083.2 → NP_001164554.1  sphingomyelin phosphodiesterase 4 isoform 3

      Status: REVIEWED

      Description
      Transcript Variant: This variant (3) lacks two alternate exons resulting in the loss of an in-frame segment in the 5' coding region, and it also lacks an alternate in-frame exon in the central coding region, compared to variant 2. The resulting isoform (3) is shorter than isoform 2.
      Source sequence(s)
      AC018804, AI393912, AK299185, DA797873
      Consensus CDS
      CCDS54398.1
      UniProtKB/Swiss-Prot
      B1PBA3, B4DM23, B4DQ31, B4DRB8, B4DWK7, B4E0L6, E7ESA2, E9PCE6, Q6FI76, Q6P1P7, Q6ZT43, Q9H0M2, Q9NW20, Q9NWL2, Q9NXE4, Q9P2C9
      Related
      ENSP00000405187.2, ENST00000431183.6
      Conserved Domains (1) summary
      pfam14724
      Location:47 → 709
      mit_SMPDase; Mitochondrial-associated sphingomyelin phosphodiesterase

    2. NM_017751.4 → NP_060221.2  sphingomyelin phosphodiesterase 4 isoform 1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) lacks an alternate in-frame exon in the central coding region, compared to variant 2, resulting in an isoform (1) that is shorter than isoform 2.
      Source sequence(s)
      AI393912, AK000304, DA797873
      Consensus CDS
      CCDS2156.2
      UniProtKB/Swiss-Prot
      B1PBA3, B4DM23, B4DQ31, B4DRB8, B4DWK7, B4E0L6, E7ESA2, E9PCE6, Q6FI76, Q6P1P7, Q6ZT43, Q9H0M2, Q9NW20, Q9NWL2, Q9NXE4, Q9P2C9
      Related
      ENSP00000259217.8, ENST00000351288.10
      Conserved Domains (1) summary
      pfam14724
      Location:47 → 782
      mit_SMPDase; Mitochondrial-associated sphingomyelin phosphodiesterase

    3. NM_017951.5 → NP_060421.3  sphingomyelin phosphodiesterase 4 isoform 2

      Status: REVIEWED

      Description
      Transcript Variant: This variant (2) encodes the longest isoform (2).
      Source sequence(s)
      AC018804
      Consensus CDS
      CCDS42751.2
      UniProtKB/Swiss-Prot
      B1PBA3, B4DM23, B4DQ31, B4DRB8, B4DWK7, B4E0L6, E7ESA2, E9PCE6, Q6FI76, Q6P1P7, Q6ZT43, Q9H0M2, Q9NW20, Q9NWL2, Q9NXE4, Q9P2C9
      UniProtKB/TrEMBL
      A0A7P0TB24
      Related
      ENSP00000506463.1, ENST00000680298.1
      Conserved Domains (1) summary
      pfam14724
      Location:8 → 772
      mit_SMPDase; Mitochondrial-associated sphingomyelin phosphodiesterase

    RNA

    1. NR_033231.3 RNA Sequence

      Status: REVIEWED

      Description
      Transcript Variant: This variant (5) lacks an alternate internal exon in the 5' region, compared to variant 2. This variant is represented as non-coding because the use of the supported translational start codon, as used in variant 2, renders the transcript a candidate for nonsense-mediated mRNA decay (NMD).
      Source sequence(s)
      AC018804, AI393912, BC064947, DA797873
      Related
      ENST00000454468.5

    2. NR_033232.3 RNA Sequence

      Status: REVIEWED

      Description
      Transcript Variant: This variant (6) lacks an alternate internal exon in both the 5' and central regions, compared to variant 2. This variant is represented as non-coding because the use of the supported translational start codon, as used in variant 2, renders the transcript a candidate for nonsense-mediated mRNA decay (NMD).
      Source sequence(s)
      AC018804, AI393912, AK303519, DA797873
      Related
      ENST00000412570.5

    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_000002.12 Reference GRCh38.p14 Primary Assembly

      Range
      130151392..130181757 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_011511444.4 → XP_011509746.1  sphingomyelin phosphodiesterase 4 isoform X2

      UniProtKB/Swiss-Prot
      B1PBA3, B4DM23, B4DQ31, B4DRB8, B4DWK7, B4E0L6, E7ESA2, E9PCE6, Q6FI76, Q6P1P7, Q6ZT43, Q9H0M2, Q9NW20, Q9NWL2, Q9NXE4, Q9P2C9
      Conserved Domains (1) summary
      pfam14724
      Location:125 → 860
      mit_SMPDase; Mitochondrial-associated sphingomyelin phosphodiesterase

    2. XM_011511443.3 → XP_011509745.1  sphingomyelin phosphodiesterase 4 isoform X1

      UniProtKB/Swiss-Prot
      B1PBA3, B4DM23, B4DQ31, B4DRB8, B4DWK7, B4E0L6, E7ESA2, E9PCE6, Q6FI76, Q6P1P7, Q6ZT43, Q9H0M2, Q9NW20, Q9NWL2, Q9NXE4, Q9P2C9
      Conserved Domains (1) summary
      pfam14724
      Location:125 → 889
      mit_SMPDase; Mitochondrial-associated sphingomyelin phosphodiesterase

    3. XM_047444938.1 → XP_047300894.1  sphingomyelin phosphodiesterase 4 isoform X3

      UniProtKB/TrEMBL
      H7C1Q6
      Related
      ENSP00000401648.1, ENST00000439886.5

    4. XM_024452978.2 → XP_024308746.1  sphingomyelin phosphodiesterase 4 isoform X4

      Conserved Domains (1) summary
      pfam14724
      Location:97 → 552
      mit_SMPDase; Mitochondrial-associated sphingomyelin phosphodiesterase

    Reference GRCh38.p14 PATCHES

    Genomic

    1. NW_025791762.1 Reference GRCh38.p14 PATCHES

      Range
      327940..358309 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_054332880.1 → XP_054188855.1  sphingomyelin phosphodiesterase 4 isoform X8

      UniProtKB/TrEMBL
      A0A7P0T9J6

    2. XM_054332879.1 → XP_054188854.1  sphingomyelin phosphodiesterase 4 isoform X7

      UniProtKB/Swiss-Prot
      B1PBA3, B4DM23, B4DQ31, B4DRB8, B4DWK7, B4E0L6, E7ESA2, E9PCE6, Q6FI76, Q6P1P7, Q6ZT43, Q9H0M2, Q9NW20, Q9NWL2, Q9NXE4, Q9P2C9

    3. XM_054332878.1 → XP_054188853.1  sphingomyelin phosphodiesterase 4 isoform X2

      UniProtKB/Swiss-Prot
      B1PBA3, B4DM23, B4DQ31, B4DRB8, B4DWK7, B4E0L6, E7ESA2, E9PCE6, Q6FI76, Q6P1P7, Q6ZT43, Q9H0M2, Q9NW20, Q9NWL2, Q9NXE4, Q9P2C9

    4. XM_054332876.1 → XP_054188851.1  sphingomyelin phosphodiesterase 4 isoform X6

      UniProtKB/TrEMBL
      A0A7P0T9J6

    5. XM_054332877.1 → XP_054188852.1  sphingomyelin phosphodiesterase 4 isoform X1

      UniProtKB/Swiss-Prot
      B1PBA3, B4DM23, B4DQ31, B4DRB8, B4DWK7, B4E0L6, E7ESA2, E9PCE6, Q6FI76, Q6P1P7, Q6ZT43, Q9H0M2, Q9NW20, Q9NWL2, Q9NXE4, Q9P2C9

    6. XM_054332875.1 → XP_054188850.1  sphingomyelin phosphodiesterase 4 isoform X5

      UniProtKB/Swiss-Prot
      B1PBA3, B4DM23, B4DQ31, B4DRB8, B4DWK7, B4E0L6, E7ESA2, E9PCE6, Q6FI76, Q6P1P7, Q6ZT43, Q9H0M2, Q9NW20, Q9NWL2, Q9NXE4, Q9P2C9

    7. XM_054332881.1 → XP_054188856.1  sphingomyelin phosphodiesterase 4 isoform X9

      UniProtKB/TrEMBL
      H7C1Q6

    8. XM_054332883.1 → XP_054188858.1  sphingomyelin phosphodiesterase 4 isoform X4

    9. XM_054332882.1 → XP_054188857.1  sphingomyelin phosphodiesterase 4 isoform X10

    10. XM_054332884.1 → XP_054188859.1  sphingomyelin phosphodiesterase 4 isoform X11

      UniProtKB/TrEMBL
      A0A7P0TB44

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060926.1 Alternate T2T-CHM13v2.0

      Range
      130585291..130615727 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_054342867.1 → XP_054198842.1  sphingomyelin phosphodiesterase 4 isoform X13

      UniProtKB/TrEMBL
      A0A7P0T9J6

    2. XM_054342866.1 → XP_054198841.1  sphingomyelin phosphodiesterase 4 isoform X12

      UniProtKB/Swiss-Prot
      B1PBA3, B4DM23, B4DQ31, B4DRB8, B4DWK7, B4E0L6, E7ESA2, E9PCE6, Q6FI76, Q6P1P7, Q6ZT43, Q9H0M2, Q9NW20, Q9NWL2, Q9NXE4, Q9P2C9

    3. XM_054342869.1 → XP_054198844.1  sphingomyelin phosphodiesterase 4 isoform X2

      UniProtKB/Swiss-Prot
      B1PBA3, B4DM23, B4DQ31, B4DRB8, B4DWK7, B4E0L6, E7ESA2, E9PCE6, Q6FI76, Q6P1P7, Q6ZT43, Q9H0M2, Q9NW20, Q9NWL2, Q9NXE4, Q9P2C9

    4. XM_054342868.1 → XP_054198843.1  sphingomyelin phosphodiesterase 4 isoform X1

      UniProtKB/Swiss-Prot
      B1PBA3, B4DM23, B4DQ31, B4DRB8, B4DWK7, B4E0L6, E7ESA2, E9PCE6, Q6FI76, Q6P1P7, Q6ZT43, Q9H0M2, Q9NW20, Q9NWL2, Q9NXE4, Q9P2C9

    5. XM_054342871.1 → XP_054198846.1  sphingomyelin phosphodiesterase 4 isoform X15

      UniProtKB/TrEMBL
      A0A7P0T9J6

    6. XM_054342870.1 → XP_054198845.1  sphingomyelin phosphodiesterase 4 isoform X14

      UniProtKB/Swiss-Prot
      B1PBA3, B4DM23, B4DQ31, B4DRB8, B4DWK7, B4E0L6, E7ESA2, E9PCE6, Q6FI76, Q6P1P7, Q6ZT43, Q9H0M2, Q9NW20, Q9NWL2, Q9NXE4, Q9P2C9

    7. XM_054342872.1 → XP_054198847.1  sphingomyelin phosphodiesterase 4 isoform X16

      UniProtKB/TrEMBL
      H7C1Q6

    8. XM_054342874.1 → XP_054198849.1  sphingomyelin phosphodiesterase 4 isoform X4

    9. XM_054342873.1 → XP_054198848.1  sphingomyelin phosphodiesterase 4 isoform X17

    10. XM_054342875.1 → XP_054198850.1  sphingomyelin phosphodiesterase 4 isoform X18

      UniProtKB/TrEMBL
      A0A7P0TB44

    Suppressed Reference Sequence(s)

    The following Reference Sequences have been suppressed. Explain

    1. NM_001171084.1: Suppressed sequence

      Description
      NM_001171084.1: 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
    Q9NXE4.3 GenPept UniProtKB/Swiss-Prot:Q9NXE4

    Gene LinkOut

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

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