FMR1 |
- 3
Haplo
Score - 0
Triplo
Score
Gene Facts External Data Attribution
- HGNC Symbol
- FMR1 (HGNC:3775) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
- HGNC Name
- fragile X messenger ribonucleoprotein 1
- Gene type
- protein-coding gene
- Locus type
- gene with protein product
- Previous symbols
- POF1, POF
- Alias symbols
- FMRP, FRAXA, MGC87458
- %HI
- 2.45(Read more about the DECIPHER Haploinsufficiency Index)
- pLI
- 0.65(Read more about gnomAD pLI score)
- LOEUF
- 0.42(Read more about gnomAD LOEUF score)
- Cytoband
- Xq27.3
- Genomic Coordinates
-
GRCh37/hg19: chrX:146993437-147032645 NCBI Ensembl UCSC GRCh38/hg38: chrX:147911919-147951125 NCBI Ensembl UCSC - MANE Select Transcript
- NM_002024.6 ENST00000370475.9 (Read more about MANE Select)
- 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 target mRNAs (PubMed:12417522, PubMed:16631377, PubMed:18653529, PubMed:19166269, PubMed:23235829, PubMed:25464849). Acts as an mRNA regulator by mediating formation of some phase- separated membraneless compartment: undergoes l... (Source: Uniprot)
Dosage Sensitivity Summary (Gene)
Haploinsufficiency (HI) Score Details
- fragile X syndrome Monarch
-
PUBMED:
1642231
Wohrle et al (1992) describes a male born to healthy non consanguineous parents presenting with global developmental delay including speech delay. Height and weight was within normal range, stature was tall with rounded shoulders. The face was course with a long jaw and high wide forehead. Ears are large and testicle size was above the 90th percentile. Proband’s younger sister was described as healthy. Cytogenetics revealed a normal male karyotype. Southern blot analysis performed to detect amplification of the CGG repeats of the FMR1 gene revealed a deletion of the CGG repeat sequence. RFLP studies of the proband, proband’s mother, and proband’s sister identified the deletion observed in the proband to be de novo. Pulse field gel (PFG) electrophoresis and PCR estimated the deletion to be less than 250-kb in size extending from ~185-kb upstream of FMR1 (DXS548 marker) to intron 3 of FMR1. No additional genes are included in this deletion.
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PUBMED:
7670500
Lugenbeel et al (1995) describes two unrelated males with features “highly suggestive of Fragile X syndrome”. Chromosomes were normal (46,XY) and FMR1 CGG repeat analysis by Southern blot analysis was within normal limits for both subjects. FMR1 protein expression was negative for both subjects interrogated by Western blot analysis. Subject 1 was identified to have a single nucleotide (frameshift) deletion in exon 5. Analysis of subject 1’s mother revealed that the frameshift deletion was de novo. Subject 2 was determined to have a two nucleotide missense change leading to aberrant splicing and premature termination. This variant was observed to be inherited from subject 2’s mildly affected mother. Subject 2’s half-sister, maternal aunt, and maternal grandmother were determined to be non-carriers of the two nucleotide deletion.
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PUBMED:
8069307
Meljer et al (1994) describes a three-generation family. Within this family 4 males and 2 females presented with characteristic Fragile X phenotype (all related). All affected males (patients 14, 15, 23, and 24-proband) and three phenotypically normal obligate carrier females (patients 3, 6, and 7) were identified to harbor a 1.6-kb deletion (ChrX:146,991,883-146,993,569)which includes FMR1-AS1, a long non-coding RNA and a portion of the 5’UTR of FMR1. The deletion was not observed in three unaffected males (patients 5, 12, and 13). Of note, patient 12 was not related to the family. Based on the pedigree it was suspected that the deletion was inherited from the deceased maternal grandfather (patient 2) of the male proband (patient 24). The deceased maternal grandfather (patient 24) was retrospectively concluded to have a normal appearance, intelligence, and behavior. It was suspected that the maternal grandfather was a germline mosaic for the 1.6-kb deletion. FMR1 mRNA expression was absent in all four affected males (patients 14, 15, 23, and 24-proband). FMR1 mRNA expression was present in normal controls and absent in two CGG expanded positive controls. It’s unclear if family members 1, 17, 18, 19, 20, and 21 are negative for the deletion or were not tested.
The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.
Triplosensitivity (TS) Score Details
The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.