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GeneBe

15-60499914-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_134261.3(RORA):c.1385G>A(p.Arg462Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000412 in 1,455,734 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

RORA
NM_134261.3 missense

Scores

2
11
6

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 5.94
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 Likely_benign. Variant got -4 ACMG points.

BS2
High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RORANM_134261.3 linkuse as main transcriptc.1385G>A p.Arg462Gln missense_variant 10/11 ENST00000335670.11
RORA-AS1NR_120342.1 linkuse as main transcriptn.290-10494C>T intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RORAENST00000335670.11 linkuse as main transcriptc.1385G>A p.Arg462Gln missense_variant 10/111 NM_134261.3 P35398-2
RORA-AS1ENST00000559824.5 linkuse as main transcriptn.290-10494C>T intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249100
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
134764
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000884
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000412
AC:
6
AN:
1455734
Hom.:
0
Cov.:
28
AF XY:
0.00000552
AC XY:
4
AN XY:
724630
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000361
Gnomad4 OTH exome
AF:
0.0000332
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.0000189

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Intellectual developmental disorder with or without epilepsy or cerebellar ataxia Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJul 27, 2018- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxNov 06, 2023Published functional studies suggest R462Q acts as a loss of function variant (PMID: 29656859); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28714951, 28191890, 31785789, 29656859) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Pathogenic
0.26
D
BayesDel_noAF
Uncertain
0.13
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.42
T;.;.;.
Eigen
Uncertain
0.25
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.95
D;D;D;D
M_CAP
Uncertain
0.099
D
MetaRNN
Uncertain
0.58
D;D;D;D
MetaSVM
Uncertain
0.52
D
MutationAssessor
Benign
1.7
L;.;.;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.89
D
PROVEAN
Benign
-0.72
N;N;N;N
REVEL
Uncertain
0.47
Sift
Benign
0.28
T;T;T;T
Sift4G
Benign
0.64
T;T;T;T
Vest4
0.64
MVP
0.72
MPC
1.2
ClinPred
0.85
D
GERP RS
5.7
Varity_R
0.56
gMVP
0.42

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs1433850094; hg19: chr15-60792113; COSMIC: COSV55035622; API