RBM8A
protein-codingRNA binding motif protein 8A, the group of RNA binding motif containing|Spliceosomal P complex|Exon junction complex
Gene summary
This gene encodes a protein with a conserved RNA-binding motif. The protein is found predominantly in the nucleus, although it is also present in the cytoplasm. It is preferentially associated with mRNAs produced by splicing, including both nuclear mRNAs and newly exported cytoplasmic mRNAs. It is thought that the protein remains associated with spliced mRNAs as a tag to indicate where introns had been present, thus coupling pre- and post-mRNA splicing events. Previously, it was thought that two genes encode this protein, RBM8A and RBM8B; it is now thought that the RBM8B locus is a pseudogene. There are two alternate translation start codons with this gene, which result in two forms of the protein. An allele mutation and a low-frequency noncoding single-nucleotide polymorphism (SNP) in this gene cause thrombocytopenia-absent radius (TAR) syndrome. [provided by RefSeq, Jul 2013]
- RBM8
MANE transcript
Inheritance
ClinVar variants
Top phenotype
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~6.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0010121
Submitter: ClinGen
RBM8A was first reported in relation to autosomal recessive thrombocytopenia-absent radius syndrome (TAR) in 2007 (Klopocki E, et al., 2007, PMID: 17236129) when a heterozygous 1q21.1 microdeletion was associated with the syndrome. In 2012 (Albers CA, et al., 2012, PMID: 22366785) the mechanism was clarified as compound inheritance of a null mutation and a low frequency regulatory SNP. The null allele in the vast majority of cases is a 1q21.1 microdeletion spanning at least 200kb and including at least 12 genes in addition to RBM8A. Seventeen additional genes commonly included in these deletions (NBPF10, HJV, TXNIP, POLR3GL, ANKRD34A, LIX1L, GNRHR3, PEX11B, ITGA11, ANKRD36, PIAS4, NUD18, POLR3C, RNF115, CD160, PDZK1, and GPR89A) have been evaluated to assess the impact of the loss of the additional material and found to have no known association with TAR, based on lack of associated coding sequence mutations (via candidate gene sequencing in PMID: 17236129 and exome sequencing in PMID: 22366785), or the predominant phenotypes of bilateral radial aplasia and thrombocytopenia, based on associations reported in OMIM or ORPHANET and a literature review. Additionally, four cases of TAR with non-deletion RBM8A null alleles strengthen the evidence that RBM8A is the associated gene within the 1q21.1 deletion (PMIDs: 22366785, 32227665). In addition to the 1q21.1 deletion alleles, at least 9 unique variants (1 frameshift, 1 nonsense, 2 splicing, and 5 regulatory SNPs located in the 5’UTR, first intron, or 3’UTR) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 10 probands, where both variants have been described, in 8 publications (PMIDs: 22366785, 24053387, 32227665, 32109542, 24220582, 26550033, 32127157, 28690869). Variants in this gene segregated with disease in 3 additional family members. This gene-disease relationship is supported by the expression of RBM8A in relevant tissues, the functional alteration in megakaryocytopoiesis of patient cells (PMID: 10688818), and some phenotypic consistency with animal models (PMIDs: 22366785, 11696323, 25948253). In summary, RBM8A is definitively associated with autosomal recessive TAR.
Inheritance Pattern: AR
Disease ID:MONDO:0010121
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0010121
Submitter: Laboratory for Molecular Medicine
This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.
Inheritance Pattern: AR
Disease ID:MONDO:0010121
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0010121
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0010121
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0010121
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Hematologic; Musculoskeletal
Intervention: Hematologic
Rationale: The condition can involve severe thrombocytopenia and bleeding episodes, and awareness may enable measures to prevent and better manage hematologic sequelae
Comments: The cause typically involves compound heterozygosity for a null variant (including a mult-gene deletion) affecting one allele and a rare non-coding variant affecting the other RBM8A allele
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to RBM8A variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005105.5. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 21 | 22 | |||
| missense | 19 | 1 | 20 | |||
| nonsense | 1 | 1 | 2 | |||
| start loss | 0 | |||||
| frameshift | 1 | 1 | 1 | 3 | ||
| splice donor/acceptor (+/-2bp) | 2 | 1 | 3 | |||
| Total | 4 | 3 | 21 | 22 | 0 | 50 |
Highest pathogenic variant AF is 0.004824785
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005096.1 | 6 | MANE Select | |
| Ensembl | ENSP00000463058.2 | 6 | MANE Select | |
| Ensembl | ENSP00000358313.3 | 6 | Standard | |
| Ensembl | ENSP00000358313.3 | 6 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- mRNA surveillance pathway - Homo sapiens (human)
- RNA transport - Homo sapiens (human)
- Spliceosome - Homo sapiens (human)
- Gene expression (Transcription)
- RNA Polymerase II Transcription
Biological Process
- nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
- regulation of alternative mRNA splicing, via spliceosome
- mRNA splicing, via spliceosome
- RNA export from nucleus
- mRNA export from nucleus
Molecular Function
- RNA binding
- mRNA binding
- protein binding
Cellular Component
- nucleus
- nucleoplasm
- cytoplasm
- cytosol
- nuclear speck
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Core component of the splicing-dependent multiprotein exon junction complex (EJC) deposited at splice junctions on mRNAs. The EJC is a dynamic structure consisting of core proteins and several peripheral nuclear and cytoplasmic associated factors that join the complex only transiently either during EJC assembly or during subsequent mRNA metabolism. The EJC marks the position of the exon-exon junction in the mature mRNA for the gene expression machinery and the core components remain bound to spliced mRNAs throughout all stages of mRNA metabolism thereby influencing downstream processes including nuclear mRNA export, subcellular mRNA localization, translation efficiency and nonsense-mediated mRNA decay (NMD). The MAGOH-RBM8A heterodimer inhibits the ATPase activity of EIF4A3, thereby trapping the ATP- bound EJC core onto spliced mRNA in a stable conformation. The MAGOH-RBM8A heterodimer interacts with the EJC key regulator PYM1 leading to EJC disassembly in the cytoplasm and translation enhancement of EJC-bearing spliced mRNAs by recruiting them to the ribosomal 48S preinitiation complex. Its removal from cytoplasmic mRNAs requires translation initiation from EJC-bearing spliced mRNAs. Associates preferentially with mRNAs produced by splicing. Does not interact with pre-mRNAs, introns, or mRNAs produced from intronless cDNAs. Associates with both nuclear mRNAs and newly exported cytoplasmic mRNAs. The MAGOH-RBM8A heterodimer is a component of the nonsense mediated decay (NMD) pathway. Involved in the splicing modulation of BCL2L1/Bcl-X (and probably other apoptotic genes); specifically inhibits formation of proapoptotic isoforms such as Bcl-X(S); the function is different from the established EJC assembly. {ECO:0000269|PubMed:12121612, ECO:0000269|PubMed:12718880, ECO:0000269|PubMed:12730685, ECO:0000269|PubMed:16209946, ECO:0000269|PubMed:19409878, ECO:0000269|PubMed:22203037}.;
Recessive Scores
- pRec
- 0.149
Intolerance Scores
- RVIS EVS
- -0.08
- RVIS percentile EVS
- 47.79
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- N
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.895
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Low | Low | Low |
| Primary Immunodeficiency | Medium | Low | Medium |
| Cancer | Low | Low | Low |