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GeneBe

15-60497580-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The NM_134261.3(RORA):c.1447C>T(p.Arg483Ter) variant causes a stop gained change. 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 Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

RORA
NM_134261.3 stop_gained

Scores

5
1
1

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.80
Variant links:
Genes affected
RORA (HGNC:10258): (RAR related orphan receptor A) The protein encoded by this gene is a member of the NR1 subfamily of nuclear hormone receptors. It can bind as a monomer or as a homodimer to hormone response elements upstream of several genes to enhance the expression of those genes. The encoded protein has been shown to interact with NM23-2, a nucleoside diphosphate kinase involved in organogenesis and differentiation, as well as with NM23-1, the product of a tumor metastasis suppressor candidate gene. Also, it has been shown to aid in the transcriptional regulation of some genes involved in circadian rhythm. Four transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Feb 2014]
RORA-AS1 (HGNC:51410): (RORA antisense RNA 1)

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0795 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RORANM_134261.3 linkuse as main transcriptc.1447C>T p.Arg483Ter stop_gained 11/11 ENST00000335670.11
RORA-AS1NR_120342.1 linkuse as main transcriptn.289+8989G>A intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RORAENST00000335670.11 linkuse as main transcriptc.1447C>T p.Arg483Ter stop_gained 11/111 NM_134261.3 P35398-2
RORA-AS1ENST00000559824.5 linkuse as main transcriptn.289+8989G>A intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Intellectual developmental disorder with or without epilepsy or cerebellar ataxia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterJan 01, 2019- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJul 25, 2022In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 982776). This variant has not been reported in the literature in individuals affected with RORA-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg516*) in the RORA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 41 amino acid(s) of the RORA protein. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.65
CADD
Pathogenic
45
DANN
Uncertain
1.0
Eigen
Pathogenic
0.98
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Pathogenic
0.97
D
MutationTaster
Benign
1.0
D;D;D;D
Vest4
0.83
GERP RS
6.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.11
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2065199547; hg19: chr15-60789779; COSMIC: COSV55036874; API