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NRCAM (neuronal cell adhesion molecule)

Written2009-02Justyna Janik, Barbara Czarnocka
Department of Biochemistry, Molecular Biology, Medical Centre of Postgraduate Education, ul. Marymoncka 99/103, 01-813 Warsaw, Poland

(Note : for Links provided by Atlas : click)

Identity

Alias_symbol (synonym)KIAA0343
Bravo
Other aliasNr-CAM
HGNC (Hugo) NRCAM
LocusID (NCBI) 4897
Atlas_Id 41578
Location 7q31.1  [Link to chromosome band 7q31]
Location_base_pair Starts at 107788071 and ends at 107880614 bp from pter ( according to hg19-Feb_2009)  [Mapping NRCAM.png]
Fusion genes
(updated 2016)
NRCAM (7q31.1) / ADORA1 (1q32.1)NRCAM (7q31.1) / NRCAM (7q31.1)NRCAM (7q31.1) / PNPLA8 (7q31.1)
NRCAM (7q31.1) / RACK1 (5q35.3)NRCAM (7q31.1) / TLN1 (9p13.3)

DNA/RNA

 
  Cartoon of the distribution of NrCAM exons, including those used in most transcripts (open boxes) and those that are alternatively spliced (filled boxes). Most exons are conserved in human, mouse and rat. Exons 1b and 33 have not been identified in humans. The candidate alternatively transcribed exons produce the shorter rat and human isoforms are shown in the bottom two rows. (Rows 3-8) NrCAM clones (Nc)1, 3, 6, 7, 14, 17 that represent splice variant isoforms identified in rat brain cDNAs. (Rows 9-10) Shorter NrCAM gene product expressed isoforms that are identified from ESTs in rat and human databases (from Ishiguro et al., 2006).
Description The NrCAM gene is about 316 kb in length, consisting of 34 exons.
Transcription NrCAM is transcribed from a single gene and the mRNA may be alternatively processed into multiple species (Grumet et al., 1991). Different transcripts of NRCAM are produced by alternative splicing of exons 10, 19 and 27-29.
There are three main alternative spliced mRNA according to Entrez: variant A - NM_001037132.1, variant B - NM_005010.3, variant C - NM_001037133.1.

Protein

 
  Cartoon of NrCAM's structure with fibronectin, immunoglobulin, transmembrane, and intracellular (C-terminal) domains indicated. Arrows indicate sites where splice variants encode additional inserted additional amino acids. These NrCAM structures are conserved in human, mouse, and rat. (from Ishiguro et al., 2006).
Description NrCAM is a cell surface protein of the immunoglobulin superfamily, L1/neurofascin/NgCAM subgroup. The molecule is 200-220kDa transmembrane protein, which contains 5 fibronectin type-III domains, 6 Ig-like C2-type (immunoglobulin-like) domains in the extracellular region and a highly conserved cytoplasmic tail. (Grumet et al., 1991; Kayyem et al., 1992; Lane et al., 1996).
Human NrCAM has few alternatively spliced regions: AE19 adds 19 amino acids to the region between Ig domain 2 and 3; AE10 lies clearly between Ig domain 6 and the beginning of the Fn repeats; AE10K2 encompasses part of the G strand of Ig 5 and most of the A strand of Ig 6; AE12 affects the G strand of Fn III domain 4; AE93 corresponds to the entire Fn type III domain (Grumet et al.,1991; Lane et al., 1996; Wang et al., 1998).
Expression Central and peripheral nervous system, and other tissues, endothelial cells, and certain tumor cell lines and human cancers including pancreatic cancer, melanoma, renal and colon carcinoma, adrenal gland, placenta, thyroid and testis (Wang et al., 1998; Glienke et al, 2000; Dhodapkar et al., 2001; Aitkenhead et al, 2002; Conacci-Sorrell et al., 2002).
Nervous system: NrCAM is expressed in structures in the developing brain. In the floor plate NrCAM has been implicated in axonal guidance trough interaction with TAG-1/axonin-1 (Lustig et al., 2001). Moreover, NrCAM induces neurite outgrowth from dorsal root ganglia neurons. It also operates as a receptor for several different neuronal recognition molecules. NrCAM protein promotes directional signaling during nervous system development in several different regions as the spinal cord, the visual system, and the cerebellum (Lustig et al., 2001; Hutcheson et al., 2004).
Localisation Various cell compartments: external side of plasma membrane, integral to plasma membrane, neuron projection, cytoplasm, nucleus.
Function NrCAM is engaged in such biological processes as axonal fasciculation, cell-cell adhesion, central nervous system development, clustering of voltage-gated sodium channels, neuron migration, positive regulation of neuron differentiation, regulation of axon extension, and synaptogenesis. It also may play a role in the molecular assembly of the nodes of Ranvier. NrCAM effects are also linked with different recognition processes and signal transduction pathways regulating cell differentiation, proliferation, or migration (Gumbiner, 1996; Cavallaro and Christofori, 2004).
Homology - NRCAM, neuronal cell adhesion molecule, Homo sapiens
- NRCAM, neuronal cell adhesion molecule, Bos taurus
- Nrcam, neuron-glia-CAM-related cell adhesion molecule, Mus musculus
- Nrcam, neuron-glia-CAM-related cell adhesion molecule, Rattus norvegicus
- NRCAM, neuronal cell adhesion molecule, Gallus gallus
- si:dkey-240a12.1, si:dkey-240a12.1, Danio rerio
- Nrg, Neuroglian, Drosophila melanogaster
- AgaP_AGAP000720, AGAP000720-PA, Anopheles gambiae
- lad-2, L1 CAM ADhesion molecule homolog, Caenorhabditis elegans
- NRCAM, neuronal cell adhesion molecule, Pan troglodytes
- LOC475881, similar to Neuronal cell adhesion m..., Canis lupus familiaris.

Mutations

Somatic According to UniProt database there are two known somatic mutations of NrCAM gene, both related to breast cancer (Sjoblom et al., 2006). First mutation results in amino-acids change from medium size and polar His to hydrophobic Pro (H1093P) in the Fn-III 5 domain, and in consequence missing in isoform 3 and 5 NrCAM protein. Second leads to another amino-acids substitution G1116V in the Fn-III 5 domain and effects in missing of 3 and 4 isoforms.

Implicated in

Note
  
Entity Brain tumor
Disease NrCAM is over-expressed in high-grade astrocytoma, glioma and glioblastoma tumor tissues. High expression of NrCAM was also observed in cell lines derived from tumors mentioned above. Low levels of NrCAM expression were observed in neuroblastoma and meningioma. Northern blot analysis showed an alternatively spliced mRNA of 1.4 kb that could translate into a small variant of the NRCAM protein, which may be tumor-specific. Analysis of DNA from brain tumor cell lines showed that over-expression of NrCAM was not due to gene amplification. The results suggest that NrCAM is over-expressed in malignant brain tumors and can serve as a novel marker for brain tumor detection and perhaps therapy (Sehgal et al., 1998).
  
  
Entity Colon cancer
Disease NrCAM expression is induced by beta-catenin and plakoglobin in complex with LEF/TCF through activation the NrCAM promoter where several LEF/TCF binding sites are localized. Excessive activation of beta-catenin signaling is characteristic for colon cancer. Significant expression of NrCAM was demonstrated in the human colon cancer cell lines, and more importantly in colon carcinoma tissue samples but not in normal colon. The results indicate that NrCAM, as a target gene of the beta-catenin-TCF/LEF-1 pathway, may play a key role in the colon cancer tumorigenesis, probably by promoting cell growth and motility (Conacci-Sorrell at al., 2002).
  
  
Entity Melanoma
Disease Melanoma cell lines from advanced stages of human melanoma, which express high levels of NrCAM, stimulate cell growth, enhance motility, induce transformation, and produce rapidly growing tumors in nude mice, while those lacking NrCAM do not. NrCAM was found in complex with alpha4 integrin and beta1 integrin in melanoma cells, indicating that it can mediate heterophilic adhesion with extracellular matrix receptors. Suppression of NrCAM levels by small interfering RNA (siRNA) inhibits the adhesive and tumorigenic capacities of these cells, and implies that NrCAM expression is necessary for these cellular processes in melanoma cells. (Conacci-Sorrell et al., 2002 and 2005).
  
  
Entity Pancreatic carcinoma
Disease NrCAM is expressed by nonneuronal elements of human pancreas and is dysregulated in various stages of pancreatic cancer. In normal tissue, NrCAM is expressed predominantly on the surface of acinal cells, and very weekly on normal ducts. In most poorly differentiated tumors as well as human pancreatic adenocarcinoma cell lines decreased or no expression of the protein is seen, whereas the well and moderately differentiated carcinomas show elevated expression. The data indicate expression of NrCAM in normal pancreas and loss in pancreatic adenocarcinoma. Taken together, this differential tissue- and cell-specific regulation of NrCAM expression suggests that this molecule may be involved in the pathogenesis and invasive/metastatic behavior of pancreatic cancers (Dhodapkar et al., 2001).
  
  
Entity Papillary thyroid carcinoma
Disease NrCAM is over-expressed in papillary thyroid carcinoma (PTC) on both gene and protein levels. The upregulation of NrCAM gene is not related to the primary tumor stage (TNM) and size (Gorka et al., 2007). NrCAM gene over-expression in papillary thyroid carcinoma was also shown by DNA microarrays study (Jarzab et al., 2005; Delys et al., 2007). Moreover, artificially raised expression of RET/PTC1) in normal human thyrocytes, directly induces many inflammatory and tumor invasion genes including the NrCAM (Borello et al., 2005). NrCAM induction and over-expression in PTC cells regardless of the primary tumor stage suggests that this is an early event during PTC development.
  
  
Entity Autism
Disease Results from various genomic screens provide evidence for an autism susceptibility region on chromosome 7q31, which contains NRCAM gene.
According to Hutcheson et al. (2004) none of the individual polymorphisms in or surrounding NRCAM demonstrated evidence for allelic association to autism. The distinct results have been reported by Bonora et al. in 2005. Screening for mutations in unrelated individuals with autism led to identification of polymorphisms in the promoter and untranslated region of NRCAM. Results suggest that alterations in expression of NRCAM gene may be linked to autism susceptibility, and association was more significant when considering the haplotype transmission (Bonora et al., 2005).
  

Bibliography

Identification of endothelial cell genes expressed in an in vitro model of angiogenesis: induction of ESM-1, (beta)ig-h3, and NrCAM.
Aitkenhead M, Wang SJ, Nakatsu MN, Mestas J, Heard C, Hughes CC.
Microvasc Res. 2002 Mar;63(2):159-71.
PMID 11866539
 
Mutation screening and association analysis of six candidate genes for autism on chromosome 7q.
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PMID 15523497
 
Induction of a proinflammatory program in normal human thyrocytes by the RET/PTC1 oncogene.
Borrello MG, Alberti L, Fischer A, Degl'innocenti D, Ferrario C, Gariboldi M, Marchesi F, Allavena P, Greco A, Collini P, Pilotti S, Cassinelli G, Bressan P, Fugazzola L, Mantovani A, Pierotti MA.
Proc Natl Acad Sci U S A. 2005 Oct 11;102(41):14825-30. Epub 2005 Oct 3.
PMID 16203990
 
Multitasking in tumor progression: signaling functions of cell adhesion molecules.
Cavallaro U, Christofori G.
Ann N Y Acad Sci. 2004 Apr;1014:58-66.
PMID 15153420
 
The shed ectodomain of Nr-CAM stimulates cell proliferation and motility, and confers cell transformation.
Conacci-Sorrell M, Kaplan A, Raveh S, Gavert N, Sakurai T, Ben-Ze'ev A.
Cancer Res. 2005 Dec 15;65(24):11605-12.
PMID 16357171
 
Gene expression and the biological phenotype of papillary thyroid carcinomas.
Delys L, Detours V, Franc B, Thomas G, Bogdanova T, Tronko M, Libert F, Dumont JE, Maenhaut C.
Oncogene. 2007 Dec 13;26(57):7894-903. Epub 2007 Jul 9.
PMID 17621275
 
Differential expression of the cell-adhesion molecule Nr-CAM in hyperplastic and neoplastic human pancreatic tissue.
Dhodapkar KM, Friedlander D, Scholes J, Grumet M.
Hum Pathol. 2001 Apr;32(4):396-400.
PMID 11331956
 
Differential gene expression by endothelial cells in distinct angiogenic states.
Glienke J, Schmitt AO, Pilarsky C, Hinzmann B, Weiss B, Rosenthal A, Thierauch KH.
Eur J Biochem. 2000 May;267(9):2820-30.
PMID 10785405
 
NrCAM, a neuronal system cell-adhesion molecule, is induced in papillary thyroid carcinomas.
Gorka B, Skubis-Zegadlo J, Mikula M, Bardadin K, Paliczka E, Czarnocka B.
Br J Cancer. 2007 Aug 20;97(4):531-8. Epub 2007 Jul 31.
PMID 17667921
 
Structure of a new nervous system glycoprotein, Nr-CAM, and its relationship to subgroups of neural cell adhesion molecules.
Grumet M, Mauro V, Burgoon MP, Edelman GM, Cunningham BA.
J Cell Biol. 1991 Jun;113(6):1399-412.
PMID 2045418
 
Cell adhesion: the molecular basis of tissue architecture and morphogenesis.
Gumbiner BM.
Cell. 1996 Feb 9;84(3):345-57.
PMID 8608588
 
Examination of NRCAM, LRRN3, KIAA0716, and LAMB1 as autism candidate genes.
Hutcheson HB, Olson LM, Bradford Y, Folstein SE, Santangelo SL, Sutcliffe JS, Haines JL.
BMC Med Genet. 2004 May 5;5:12.
PMID 15128462
 
NrCAM in addiction vulnerability: positional cloning, drug-regulation, haplotype-specific expression, and altered drug reward in knockout mice.
Ishiguro H, Liu QR, Gong JP, Hall FS, Ujike H, Morales M, Sakurai T, Grumet M, Uhl GR.
Neuropsychopharmacology. 2006 Mar;31(3):572-84.
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Gene expression profile of papillary thyroid cancer: sources of variability and diagnostic implications.
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Cancer Res. 2005 Feb 15;65(4):1587-97.
PMID 15735049
 
Bravo/Nr-CAM is closely related to the cell adhesion molecules L1 and Ng-CAM and has a similar heterodimer structure.
Kayyem JF, Roman JM, de la Rosa EJ, Schwarz U, Dreyer WJ.
J Cell Biol. 1992 Sep;118(5):1259-70.
PMID 1512296
 
Characterization of a highly conserved human homolog to the chicken neural cell surface protein Bravo/Nr-CAM that maps to chromosome band 7q31.
Lane RP, Chen XN, Yamakawa K, Vielmetter J, Korenberg JR, Dreyer WJ.
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PMID 8812479
 
Nr-CAM expression in the developing mouse nervous system: ventral midline structures, specific fiber tracts, and neuropilar regions.
Lustig M, Erskine L, Mason CA, Grumet M, Sakurai T.
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PMID 11329126
 
Cell adhesion molecule Nr-CAM is over-expressed in human brain tumors.
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The consensus coding sequences of human breast and colorectal cancers.
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Citation

This paper should be referenced as such :
Janik, J ; Czarnocka, B
NRCAM (neuronal cell adhesion molecule)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(1):44-47.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/NRCAMID41578ch7q31.html


External links

Nomenclature
HGNC (Hugo)NRCAM   7994
Cards
AtlasNRCAMID41578ch7q31
Entrez_Gene (NCBI)NRCAM  4897  neuronal cell adhesion molecule
Aliases
GeneCards (Weizmann)NRCAM
Ensembl hg19 (Hinxton)ENSG00000091129 [Gene_View]  chr7:107788071-107880614 [Contig_View]  NRCAM [Vega]
Ensembl hg38 (Hinxton)ENSG00000091129 [Gene_View]  chr7:107788071-107880614 [Contig_View]  NRCAM [Vega]
ICGC DataPortalENSG00000091129
TCGA cBioPortalNRCAM
AceView (NCBI)NRCAM
Genatlas (Paris)NRCAM
WikiGenes4897
SOURCE (Princeton)NRCAM
Genetics Home Reference (NIH)NRCAM
Genomic and cartography
GoldenPath hg19 (UCSC)NRCAM  -     chr7:107788071-107880614 -  7q31   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)NRCAM  -     7q31   [Description]    (hg38-Dec_2013)
EnsemblNRCAM - 7q31 [CytoView hg19]  NRCAM - 7q31 [CytoView hg38]
Mapping of homologs : NCBINRCAM [Mapview hg19]  NRCAM [Mapview hg38]
OMIM601581   
Gene and transcription
Genbank (Entrez)AB002341 AI031622 AJ001054 AJ001057 AK092330
RefSeq transcript (Entrez)NM_001037132 NM_001037133 NM_001193582 NM_001193583 NM_001193584 NM_005010
RefSeq genomic (Entrez)NC_000007 NC_018918 NG_029898 NT_007933 NW_004929332
Consensus coding sequences : CCDS (NCBI)NRCAM
Cluster EST : UnigeneHs.21422 [ NCBI ]
CGAP (NCI)Hs.21422
Alternative Splicing GalleryENSG00000091129
Gene ExpressionNRCAM [ NCBI-GEO ]   NRCAM [ EBI - ARRAY_EXPRESS ]   NRCAM [ SEEK ]   NRCAM [ MEM ]
Gene Expression Viewer (FireBrowse)NRCAM [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)4897
GTEX Portal (Tissue expression)NRCAM
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ92823   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ92823  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ92823
Splice isoforms : SwissVarQ92823
PhosPhoSitePlusQ92823
Domaine pattern : Prosite (Expaxy)FN3 (PS50853)    IG_LIKE (PS50835)    IG_MHC (PS00290)   
Domains : Interpro (EBI)FN3_dom    Ig-like_dom    Ig-like_fold    Ig/MHC_CS    Ig_I-set    Ig_sub    Ig_sub2    Neurofascin/L1/NrCAM_C   
Domain families : Pfam (Sanger)Bravo_FIGEY (PF13882)    fn3 (PF00041)    I-set (PF07679)   
Domain families : Pfam (NCBI)pfam13882    pfam00041    pfam07679   
Domain families : Smart (EMBL)FN3 (SM00060)  IG (SM00409)  IGc2 (SM00408)  
Conserved Domain (NCBI)NRCAM
DMDM Disease mutations4897
Blocks (Seattle)NRCAM
PDB (SRS)1UEN    1UEY   
PDB (PDBSum)1UEN    1UEY   
PDB (IMB)1UEN    1UEY   
PDB (RSDB)1UEN    1UEY   
Structural Biology KnowledgeBase1UEN    1UEY   
SCOP (Structural Classification of Proteins)1UEN    1UEY   
CATH (Classification of proteins structures)1UEN    1UEY   
SuperfamilyQ92823
Human Protein AtlasENSG00000091129
Peptide AtlasQ92823
HPRD07207
IPIIPI00333776   IPI00333777   IPI00333778   IPI00415032   IPI00873446   IPI00926075   IPI00924735   IPI01014858   IPI01025322   IPI00983847   IPI00883753   IPI01009571   IPI00925886   IPI00927071   
Protein Interaction databases
DIP (DOE-UCLA)Q92823
IntAct (EBI)Q92823
FunCoupENSG00000091129
BioGRIDNRCAM
STRING (EMBL)NRCAM
ZODIACNRCAM
Ontologies - Pathways
QuickGOQ92823
Ontology : AmiGOangiogenesis  neuron migration  protein binding  extracellular region  plasma membrane  integral component of plasma membrane  axonogenesis  axonal fasciculation  synapse assembly  central nervous system development  protein localization  external side of plasma membrane  single organismal cell-cell adhesion  neuronal action potential propagation  ankyrin binding  regulation of axon extension  retinal ganglion cell axon guidance  heterotypic cell-cell adhesion  neuron projection  axon initial segment  clustering of voltage-gated sodium channels  synapse  positive regulation of neuron differentiation  protein binding involved in heterotypic cell-cell adhesion  
Ontology : EGO-EBIangiogenesis  neuron migration  protein binding  extracellular region  plasma membrane  integral component of plasma membrane  axonogenesis  axonal fasciculation  synapse assembly  central nervous system development  protein localization  external side of plasma membrane  single organismal cell-cell adhesion  neuronal action potential propagation  ankyrin binding  regulation of axon extension  retinal ganglion cell axon guidance  heterotypic cell-cell adhesion  neuron projection  axon initial segment  clustering of voltage-gated sodium channels  synapse  positive regulation of neuron differentiation  protein binding involved in heterotypic cell-cell adhesion  
Pathways : KEGGCell adhesion molecules (CAMs)   
REACTOMEQ92823 [protein]
REACTOME Pathways445095 [pathway]   447038 [pathway]   447043 [pathway]   
NDEx NetworkNRCAM
Atlas of Cancer Signalling NetworkNRCAM
Wikipedia pathwaysNRCAM
Orthology - Evolution
OrthoDB4897
GeneTree (enSembl)ENSG00000091129
Phylogenetic Trees/Animal Genes : TreeFamNRCAM
HOVERGENQ92823
HOGENOMQ92823
Homologs : HomoloGeneNRCAM
Homology/Alignments : Family Browser (UCSC)NRCAM
Gene fusions - Rearrangements
Fusion : MitelmanNRCAM/TLN1 [7q31.1/9p13.3]  
Fusion: TCGANRCAM 7q31.1 TLN1 9p13.3 LGG
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerNRCAM [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)NRCAM
dbVarNRCAM
ClinVarNRCAM
1000_GenomesNRCAM 
Exome Variant ServerNRCAM
ExAC (Exome Aggregation Consortium)NRCAM (select the gene name)
Genetic variants : HAPMAP4897
Genomic Variants (DGV)NRCAM [DGVbeta]
DECIPHER (Syndromes)7:107788071-107880614  ENSG00000091129
CONAN: Copy Number AnalysisNRCAM 
Mutations
ICGC Data PortalNRCAM 
TCGA Data PortalNRCAM 
Broad Tumor PortalNRCAM
OASIS PortalNRCAM [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICNRCAM  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDNRCAM
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch NRCAM
DgiDB (Drug Gene Interaction Database)NRCAM
DoCM (Curated mutations)NRCAM (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)NRCAM (select a term)
intoGenNRCAM
NCG5 (London)NRCAM
Cancer3DNRCAM(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM601581   
Orphanet
MedgenNRCAM
Genetic Testing Registry NRCAM
NextProtQ92823 [Medical]
TSGene4897
GENETestsNRCAM
Huge Navigator NRCAM [HugePedia]
snp3D : Map Gene to Disease4897
BioCentury BCIQNRCAM
ClinGenNRCAM
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD4897
Chemical/Pharm GKB GenePA31773
Clinical trialNRCAM
Miscellaneous
canSAR (ICR)NRCAM (select the gene name)
Probes
Litterature
PubMed45 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineNRCAM
EVEXNRCAM
GoPubMedNRCAM
iHOPNRCAM
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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