rs1433850094

Variant names:

• chr15-60499914-C-T
• rs1433850094
• NM_134261.3:c.1385G>A

Variant summary

Our verdict is Likely benign. The variant received -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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:2
• Conservation: PhyloP100: 5.94
• Publications: 4 publications found

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)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_134261.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RORA	NM_134261.3	MANE Select	c.1385G>A	p.Arg462Gln	missense	Exon 10 of 11	NP_599023.1	P35398-2
	RORA	NM_134260.3		c.1484G>A	p.Arg495Gln	missense	Exon 11 of 12	NP_599022.1	P35398-1
	RORA	NM_002943.4		c.1460G>A	p.Arg487Gln	missense	Exon 10 of 11	NP_002934.1	A0A0C4DFP5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RORA	ENST00000335670.11	TSL:1 MANE Select	c.1385G>A	p.Arg462Gln	missense	Exon 10 of 11	ENSP00000335087.6	P35398-2
	RORA	ENST00000261523.9	TSL:1	c.1484G>A	p.Arg495Gln	missense	Exon 11 of 12	ENSP00000261523.5	P35398-1
	RORA	ENST00000309157.8	TSL:1	c.1460G>A	p.Arg487Gln	missense	Exon 10 of 11	ENSP00000309753.3	A0A0C4DFP5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249100 AF XY: 0.00

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33178

American (AMR) AF: 0.00 AC: 0 AN: 44230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26020

East Asian (EAS) AF: 0.00 AC: 0 AN: 39604

South Asian (SAS) AF: 0.00 AC: 0 AN: 85980

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53146

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1107678

Other (OTH) AF: 0.0000332 AC: 2 AN: 60152

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	1	-	Intellectual developmental disorder with or without epilepsy or cerebellar ataxia (2)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Uncertain	0.099	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Benign	1.7	L
PhyloP100		5.9
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.72	N
REVEL	Uncertain	0.47
Sift	Benign	0.28	T
Sift4G	Benign	0.64	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
Mutation Taster		=8/92	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1433850094; hg19: chr15-60792113; COSMIC: COSV55035622;