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GeneBe

15-60499902-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_134261.3(RORA):c.1397T>C(p.Ile466Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,828 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: 6.9e-7 ( 0 hom. )

Consequence

RORA
NM_134261.3 missense

Scores

4
6
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.25
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 2 ACMG points.

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.1397T>C p.Ile466Thr missense_variant 10/11 ENST00000335670.11
RORA-AS1NR_120342.1 linkuse as main transcriptn.290-10506A>G intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RORAENST00000335670.11 linkuse as main transcriptc.1397T>C p.Ile466Thr missense_variant 10/111 NM_134261.3 P35398-2
RORA-AS1ENST00000559824.5 linkuse as main transcriptn.290-10506A>G intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.93e-7
AC:
1
AN:
1443828
Hom.:
0
Cov.:
27
AF XY:
0.00000139
AC XY:
1
AN XY:
719556
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:
9.11e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000611
Hom.:
0

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxDec 03, 2019Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.25
BayesDel_addAF
Pathogenic
0.33
D
BayesDel_noAF
Pathogenic
0.24
CADD
Benign
23
DANN
Uncertain
0.98
DEOGEN2
Benign
0.40
T;.;.;.
Eigen
Benign
0.014
Eigen_PC
Uncertain
0.24
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.81
T;T;T;T
M_CAP
Uncertain
0.11
D
MetaRNN
Uncertain
0.63
D;D;D;D
MetaSVM
Uncertain
0.33
D
MutationAssessor
Benign
0.94
L;.;.;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.90
D
PROVEAN
Benign
-0.74
N;N;N;N
REVEL
Uncertain
0.54
Sift
Benign
0.27
T;T;T;T
Sift4G
Benign
0.21
T;T;T;T
Vest4
0.82
MVP
0.94
MPC
1.2
ClinPred
0.76
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.40
gMVP
0.47

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-60792101; API