FMR1
fragile X messenger ribonucleoprotein 1
Basic information
Region (hg38): X:147911919-147951125
Previous symbols: [ "POF1", "POF" ]
Links
Phenotypes
GenCC
Source:
- fragile X syndrome (Definitive), mode of inheritance: XL
- fragile X syndrome (Definitive), mode of inheritance: XLR
- premature ovarian failure 1 (Strong), mode of inheritance: XL
- fragile X syndrome (Definitive), mode of inheritance: XL
- fragile X-associated tremor/ataxia syndrome (Strong), mode of inheritance: XL
- fragile X syndrome (Supportive), mode of inheritance: XL
- fragile X-associated tremor/ataxia syndrome (Supportive), mode of inheritance: XL
- symptomatic form of fragile X syndrome in female carrier (Supportive), mode of inheritance: XL
- fragile X-associated tremor/ataxia syndrome (Definitive), mode of inheritance: XL
- fragile X syndrome (Definitive), mode of inheritance: XL
- premature ovarian failure 1 (Definitive), mode of inheritance: XL
- fragile X syndrome (Strong), mode of inheritance: XL
- fragile X-associated tremor/ataxia syndrome (Strong), mode of inheritance: XL
- premature ovarian failure 1 (Strong), mode of inheritance: XL
- fragile X syndrome (Definitive), mode of inheritance: XL
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Premature ovarian failure 1 | XL | Obstetric | Genetic knowledge may be beneficial to allow interventions such as preserving eggs in women with premature ovarian insufficiency | Craniofacial; Endocrine; Neurologic; Obstetric | 5794013; 7333582; 6958915; 6711591; 3398009; 2195034; 1944467; 9719368; 10208170; 10325264; 11445641; 12730995; 12638084; 12533098; 14747503; 15065016; 15052536; 16043804; 16493202; 17166801; 18348275; 19724010; 19411303; 20228389; 19542082; 21518720; 21188402; 21300345; 21912443; 23703681 |
ClinVar
This is a list of variants' phenotypes submitted to
- Intellectual disability (2 variants)
- not provided (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the FMR1 gene is commonly pathogenic or not.
In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.
Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.
| Variant type | Pathogenic | Likely pathogenic | VUS | Likely benign | Benign | Sum |
|---|---|---|---|---|---|---|
| synonymous | 13 | 16 | ||||
| missense | 43 | 55 | ||||
| nonsense | 1 | |||||
| start loss | 0 | |||||
| frameshift | 1 | |||||
| inframe indel | 0 | |||||
| splice donor/acceptor (+/-2bp) | 6 | |||||
| splice region | 1 | 2 | 1 | 1 | 5 | |
| non coding | 59 | 68 | ||||
| Total | 2 | 6 | 48 | 29 | 62 |
Variants in FMR1
This is a list of pathogenic ClinVar variants found in the FMR1 region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| FMR1 | protein_coding | protein_coding | ENST00000370475 | 17 | 39177 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 0.647 | 0.353 | 125508 | 86 | 152 | 125746 | 0.000947 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 2.97 | 118 | 250 | 0.471 | 0.0000197 | 4157 |
| Missense in Polyphen | 22 | 84.072 | 0.26168 | 1230 | ||
| Synonymous | 1.40 | 67 | 83.2 | 0.805 | 0.00000632 | 1189 |
| Loss of Function | 3.73 | 5 | 25.2 | 0.198 | 0.00000187 | 450 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.000152 | 0.000123 |
| Ashkenazi Jewish | 0.00 | 0.00 |
| East Asian | 0.00 | 0.00 |
| Finnish | 0.0112 | 0.00835 |
| European (Non-Finnish) | 0.000574 | 0.000413 |
| Middle Eastern | 0.00 | 0.00 |
| South Asian | 0.000105 | 0.0000653 |
| Other | 0.00154 | 0.00114 |
dbNSFP
Source:
- Function
- FUNCTION: Multifunctional polyribosome-associated RNA-binding protein that plays a central role in neuronal development and synaptic plasticity through the regulation of alternative mRNA splicing, mRNA stability, mRNA dendritic transport and postsynaptic local protein synthesis of a subset of mRNAs (PubMed:16631377, PubMed:18653529, PubMed:19166269, PubMed:23235829, PubMed:25464849). Plays a role in the alternative splicing of its own mRNA (PubMed:18653529). Plays a role in mRNA nuclear export (By similarity). Together with export factor NXF2, is involved in the regulation of the NXF1 mRNA stability in neurons (By similarity). Stabilizes the scaffolding postsynaptic density protein DLG4/PSD-95 and the myelin basic protein (MBP) mRNAs in hippocampal neurons and glial cells, respectively; this stabilization is further increased in response to metabotropic glutamate receptor (mGluR) stimulation (By similarity). Plays a role in selective delivery of a subset of dendritic mRNAs to synaptic sites in response to mGluR activation in a kinesin- dependent manner (By similarity). Plays a role as a repressor of mRNA translation during the transport of dendritic mRNAs to postnyaptic dendritic spines (PubMed:11532944, PubMed:11157796, PubMed:12594214, PubMed:23235829). Component of the CYFIP1-EIF4E- FMR1 complex which blocks cap-dependent mRNA translation initiation (By similarity). Represses mRNA translation by stalling ribosomal translocation during elongation (By similarity). Reports are contradictory with regards to its ability to mediate translation inhibition of MBP mRNA in oligodendrocytes (PubMed:23891804). Also involved in the recruitment of the RNA helicase MOV10 to a subset of mRNAs and hence regulates microRNA (miRNA)-mediated translational repression by AGO2 (PubMed:14703574, PubMed:17057366, PubMed:25464849). Facilitates the assembly of miRNAs on specific target mRNAs (PubMed:17057366). Plays also a role as an activator of mRNA translation of a subset of dendritic mRNAs at synapses (PubMed:19097999, PubMed:19166269). In response to mGluR stimulation, FMR1-target mRNAs are rapidly derepressed, allowing for local translation at synapses (By similarity). Binds to a large subset of dendritic mRNAs that encode a myriad of proteins involved in pre- and postsynaptic functions (PubMed:7692601, PubMed:11719189, PubMed:11157796, PubMed:12594214, PubMed:17417632, PubMed:23235829, PubMed:24448548). Binds to 5'-ACU[GU]-3' and/or 5'-[AU]GGA-3' RNA consensus sequences within mRNA targets, mainly at coding sequence (CDS) and 3'-untranslated region (UTR) and less frequently at 5'- UTR (PubMed:23235829). Binds to intramolecular G-quadruplex structures in the 5'- or 3'-UTRs of mRNA targets (PubMed:11719189, PubMed:18579868, PubMed:25464849, PubMed:25692235). Binds to G- quadruplex structures in the 3'-UTR of its own mRNA (PubMed:7692601, PubMed:11532944, PubMed:12594214, PubMed:15282548, PubMed:18653529). Binds also to RNA ligands harboring a kissing complex (kc) structure; this binding may mediate the association of FMR1 with polyribosomes (PubMed:15805463). Binds mRNAs containing U-rich target sequences (PubMed:12927206). Binds to a triple stem-loop RNA structure, called Sod1 stem loop interacting with FMRP (SoSLIP), in the 5'- UTR region of superoxide dismutase SOD1 mRNA (PubMed:19166269). Binds to the dendritic, small non-coding brain cytoplasmic RNA 1 (BC1); which may increase the association of the CYFIP1-EIF4E-FMR1 complex to FMR1 target mRNAs at synapses (By similarity). Associates with export factor NXF1 mRNA-containing ribonucleoprotein particles (mRNPs) in a NXF2-dependent manner (By similarity). Binds to a subset of miRNAs in the brain (PubMed:14703574, PubMed:17057366). May associate with nascent transcripts in a nuclear protein NXF1-dependent manner (PubMed:18936162). In vitro, binds to RNA homopolymer; preferentially on poly(G) and to a lesser extent on poly(U), but not on poly(A) or poly(C) (PubMed:7688265, PubMed:7781595, PubMed:12950170, PubMed:15381419, PubMed:8156595). Moreover, plays a role in the modulation of the sodium-activated potassium channel KCNT1 gating activity (PubMed:20512134). Negatively regulates the voltage-dependent calcium channel current density in soma and presynaptic terminals of dorsal root ganglion (DRG) neurons, and hence regulates synaptic vesicle exocytosis (By similarity). Modulates the voltage-dependent calcium channel CACNA1B expression at the plasma membrane by targeting the channels for proteosomal degradation (By similarity). Plays a role in regulation of MAP1B- dependent microtubule dynamics during neuronal development (By similarity). Recently, has been shown to play a translation- independent role in the modulation of presynaptic action potential (AP) duration and neurotransmitter release via large-conductance calcium-activated potassium (BK) channels in hippocampal and cortical excitatory neurons (PubMed:25561520). Finally, FMR1 may be involved in the control of DNA damage response (DDR) mechanisms through the regulation of ATR-dependent signaling pathways such as histone H2AFX/H2A.x and BRCA1 phosphorylations (PubMed:24813610). {ECO:0000250|UniProtKB:P35922, ECO:0000250|UniProtKB:Q80WE1, ECO:0000269|PubMed:11157796, ECO:0000269|PubMed:11532944, ECO:0000269|PubMed:11719189, ECO:0000269|PubMed:12594214, ECO:0000269|PubMed:12927206, ECO:0000269|PubMed:12950170, ECO:0000269|PubMed:14703574, ECO:0000269|PubMed:15282548, ECO:0000269|PubMed:15381419, ECO:0000269|PubMed:15805463, ECO:0000269|PubMed:16631377, ECO:0000269|PubMed:17057366, ECO:0000269|PubMed:17417632, ECO:0000269|PubMed:18579868, ECO:0000269|PubMed:18653529, ECO:0000269|PubMed:18936162, ECO:0000269|PubMed:19097999, ECO:0000269|PubMed:19166269, ECO:0000269|PubMed:20512134, ECO:0000269|PubMed:23235829, ECO:0000269|PubMed:23891804, ECO:0000269|PubMed:24448548, ECO:0000269|PubMed:24813610, ECO:0000269|PubMed:25464849, ECO:0000269|PubMed:25561520, ECO:0000269|PubMed:25692235, ECO:0000269|PubMed:7688265, ECO:0000269|PubMed:7692601, ECO:0000269|PubMed:7781595, ECO:0000269|PubMed:8156595}.; FUNCTION: Isoform 6: binds to RNA homopolymer; preferentially on poly(G) and to a lesser extent on poly(U), but not on poly(A) or poly(C) (PubMed:24204304). May bind to RNA in Cajal bodies (PubMed:24204304). {ECO:0000269|PubMed:24204304}.;
- Disease
- DISEASE: Fragile X syndrome (FXS) [MIM:300624]: A X-linked dominant disease characterized by moderate to severe mental retardation, macroorchidism (enlargement of the testicles), large ears, prominent jaw, and high-pitched, jocular speech. The defect in most patients results from an amplification of a CGG repeat region in the FMR1 gene and abnormal methylation. {ECO:0000269|PubMed:10196376, ECO:0000269|PubMed:11157796, ECO:0000269|PubMed:15380484, ECO:0000269|PubMed:15805463, ECO:0000269|PubMed:17850748, ECO:0000269|PubMed:18093976, ECO:0000269|PubMed:18664458, ECO:0000269|PubMed:23235829, ECO:0000269|PubMed:24204304, ECO:0000269|PubMed:24448548, ECO:0000269|PubMed:24514761, ECO:0000269|PubMed:24813610, ECO:0000269|PubMed:25561520, ECO:0000269|PubMed:7633450, ECO:0000269|PubMed:7688265, ECO:0000269|PubMed:8156595, ECO:0000269|PubMed:8401578, ECO:0000269|PubMed:8490650, ECO:0000269|PubMed:9659908}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Fragile X tremor/ataxia syndrome (FXTAS) [MIM:300623]: In FXTAS, the expanded repeats range in size from 55 to 200 repeats and are referred to as 'premutations'. Full repeat expansions with greater than 200 repeats results in fragile X mental retardation syndrome [MIM:300624]. Carriers of the premutation typically do not show the full fragile X syndrome phenotype, but comprise a subgroup that may have some physical features of fragile X syndrome or mild cognitive and emotional problems. {ECO:0000269|PubMed:11445641}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Premature ovarian failure 1 (POF1) [MIM:311360]: An ovarian disorder defined as the cessation of ovarian function under the age of 40 years. It is characterized by oligomenorrhea or amenorrhea, in the presence of elevated levels of serum gonadotropins and low estradiol. {ECO:0000269|PubMed:9719368}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
- Pathway
- RNA transport - Homo sapiens (human);Serotonin and anxiety
(Consensus)
Recessive Scores
- pRec
- 0.517
Intolerance Scores
- loftool
- 0.543
- rvis_EVS
- 0.26
- rvis_percentile_EVS
- 70.26
Haploinsufficiency Scores
- pHI
- 0.580
- hipred
- Y
- hipred_score
- 0.708
- ghis
- 0.517
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.970
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Fmr1
- Phenotype
- cellular phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); endocrine/exocrine gland phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); vision/eye phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); reproductive system phenotype;
Zebrafish Information Network
- Gene name
- fmr1
- Affected structure
- Rohon-Beard neuron
- Phenotype tag
- abnormal
- Phenotype quality
- increased amount
Gene ontology
- Biological process
- regulation of alternative mRNA splicing, via spliceosome;positive regulation of protein phosphorylation;positive regulation of receptor internalization;mRNA processing;cellular response to DNA damage stimulus;glutamate receptor signaling pathway;central nervous system development;anterograde axonal transport;RNA splicing;viral process;negative regulation of translation;gene silencing by RNA;positive regulation of histone phosphorylation;cellular response to UV;regulation of mRNA stability;modulation by host of viral RNA genome replication;positive regulation of translation;negative regulation of translational initiation;regulation of neurotransmitter secretion;regulation of dendrite morphogenesis;mRNA transport;regulation of filopodium assembly;positive regulation of filopodium assembly;regulation of gene silencing by miRNA;regulation of dendritic spine development;positive regulation of dendritic spine development;cellular response to hydroxyurea;cellular response to virus;regulation of neuronal action potential;regulation of translation at postsynapse, modulating synaptic transmission;negative regulation of long-term synaptic depression;positive regulation of intracellular transport of viral material;negative regulation of voltage-gated calcium channel activity;positive regulation of proteasomal protein catabolic process;negative regulation of mRNA catabolic process;positive regulation of mRNA binding;regulation of modification of synaptic structure;negative regulation of synaptic vesicle exocytosis;positive regulation of gene silencing by miRNA;negative regulation of cytoplasmic translation;positive regulation of response to DNA damage stimulus
- Cellular component
- chromosome, centromeric region;nucleus;nucleoplasm;chromosome;nucleolus;cytoplasm;cytosol;polysome;mRNA cap binding complex;chromocenter;cytoplasmic stress granule;postsynaptic density;Cajal body;membrane;viral replication complex;extrinsic component of plasma membrane;cell junction;axon;dendrite;growth cone;filopodium tip;SMN complex;ribonucleoprotein granule;cytoplasmic ribonucleoprotein granule;presynaptic membrane;polysomal ribosome;cell projection;neuron projection;neuronal cell body;dendritic spine;perikaryon;axon terminus;dendritic spine neck;synapse;postsynaptic membrane;perinuclear region of cytoplasm;neuronal ribonucleoprotein granule;glial cell projection;presynapse;postsynapse;dendritic filopodium;axon cytoplasm;messenger ribonucleoprotein complex;growth cone filopodium;ribonucleoprotein complex
- Molecular function
- G-quadruplex RNA binding;chromatin binding;RNA binding;mRNA binding;mRNA 3'-UTR binding;protein binding;microtubule binding;poly(U) RNA binding;translation repressor activity;translation initiation factor binding;RNA strand annealing activity;poly(G) binding;methylated histone binding;siRNA binding;miRNA binding;RNA stem-loop binding;identical protein binding;protein homodimerization activity;ribosome binding;ion channel binding;translation regulator activity;protein heterodimerization activity;mRNA 5'-UTR binding;dynein complex binding;sequence-specific mRNA binding