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GeneBe

15-60499954-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_134261.3(RORA):c.1345A>G(p.Ile449Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

RORA
NM_134261.3 missense

Scores

3
4
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.95
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)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.27228194).
BS2
High AC in GnomAdExome4 at 36 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RORANM_134261.3 linkuse as main transcriptc.1345A>G p.Ile449Val missense_variant 10/11 ENST00000335670.11
RORA-AS1NR_120342.1 linkuse as main transcriptn.290-10454T>C intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RORAENST00000335670.11 linkuse as main transcriptc.1345A>G p.Ile449Val missense_variant 10/111 NM_134261.3 P35398-2
RORA-AS1ENST00000559824.5 linkuse as main transcriptn.290-10454T>C intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152138
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
250790
Hom.:
0
AF XY:
0.0000369
AC XY:
5
AN XY:
135556
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:
0.0000352
Gnomad OTH exome
AF:
0.000328
GnomAD4 exome
AF:
0.0000246
AC:
36
AN:
1461246
Hom.:
0
Cov.:
29
AF XY:
0.0000330
AC XY:
24
AN XY:
726962
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000225
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152256
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74478
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000174
Hom.:
0
Bravo
AF:
0.0000264
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.00000824
AC:
1

ClinVar

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

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 18, 2022The c.1444A>G (p.I482V) alteration is located in exon 11 (coding exon 11) of the RORA gene. This alteration results from a A to G substitution at nucleotide position 1444, causing the isoleucine (I) at amino acid position 482 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Uncertain
0.10
CADD
Benign
22
DANN
Benign
0.87
DEOGEN2
Benign
0.40
T;.;.;.
Eigen
Benign
-0.15
Eigen_PC
Benign
0.11
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.94
D;D;D;D
M_CAP
Benign
0.038
D
MetaRNN
Benign
0.27
T;T;T;T
MetaSVM
Uncertain
0.33
D
MutationAssessor
Benign
-0.37
N;.;.;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.83
D
PROVEAN
Benign
-0.070
N;N;N;N
REVEL
Uncertain
0.48
Sift
Benign
0.76
T;T;T;T
Sift4G
Benign
1.0
T;T;T;T
Vest4
0.43
MVP
0.92
MPC
0.83
ClinPred
0.12
T
GERP RS
5.7
Varity_R
0.14
gMVP
0.22

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: rs200511374; hg19: chr15-60792153; API