rs1555427498
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_ModeratePP5_Moderate
The NM_134261.3(RORA):c.275G>C(p.Gly92Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G92S) has been classified as Likely pathogenic.
Frequency
Consequence
NM_134261.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RORA | NM_134261.3 | c.275G>C | p.Gly92Ala | missense_variant | 3/11 | ENST00000335670.11 | |
RORA-AS1 | NR_120342.1 | n.415+21240C>G | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RORA | ENST00000335670.11 | c.275G>C | p.Gly92Ala | missense_variant | 3/11 | 1 | NM_134261.3 | ||
RORA-AS1 | ENST00000559824.5 | n.415+21240C>G | intron_variant, non_coding_transcript_variant | 3 | |||||
ENST00000560280.1 | n.79+1722C>G | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 25
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Intellectual developmental disorder with or without epilepsy or cerebellar ataxia Pathogenic:2
Pathogenic, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | May 27, 2020 | The heterozygous p.Gly92Ala variant in RORA was identified by our study in an individual with intellectual developmental disorder with or without epilepsy or cerebellar ataxia (PMID: 29656859). Trio exome analysis showed this variant to be de novo. This variant was absent from large population studies and has been reported pathogenic by OMIM in ClinVar (Variation ID: 549843). In vitro functional studies provide some evidence that the p.Gly92Ala variant may impact protein function (PMID: 29656859). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Gly92Ala variant is located in a region of RORA that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 29656859). In summary, this variant meets criteria to be classified as pathogenic for intellectual developmental disorder with or without epilepsy or cerebellar ataxia in an autosomal dominant manner based on an affected individual with a de novo variant and in vitro functional studies. ACMG/AMP Criteria applied: PS2, PS3, PM2, PP3, PM1_Supporting (Richards 2015). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 27, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at