15-60497599-G-T

Variant names:

• chr15-60497599-G-T
• rs11071539
• NM_134261.3:c.1428C>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_134261.3(RORA):​c.1428C>A​(p.Thr476Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.989 in 1,612,332 control chromosomes in the GnomAD database, including 790,256 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.95 (69132 hom., cov: 31)
  • Exomes 𝑓: 0.99 (721124 hom.)
• Consequence: RORA NM_134261.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0770
• Publications: 13 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 15-60497599-G-T is Benign according to our data. Variant chr15-60497599-G-T is described in ClinVar as Benign. ClinVar VariationId is 1327966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.077 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.992 is higher than 0.05.

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.1428C>A	p.Thr476Thr	synonymous	Exon 11 of 11	NP_599023.1	P35398-2
	RORA	NM_134260.3		c.1527C>A	p.Thr509Thr	synonymous	Exon 12 of 12	NP_599022.1	P35398-1
	RORA	NM_002943.4		c.1503C>A	p.Thr501Thr	synonymous	Exon 11 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.1428C>A	p.Thr476Thr	synonymous	Exon 11 of 11	ENSP00000335087.6	P35398-2
	RORA	ENST00000261523.9	TSL:1	c.1527C>A	p.Thr509Thr	synonymous	Exon 12 of 12	ENSP00000261523.5	P35398-1
	RORA	ENST00000309157.8	TSL:1	c.1503C>A	p.Thr501Thr	synonymous	Exon 11 of 11	ENSP00000309753.3	A0A0C4DFP5

Frequencies

GnomAD3 genomes AF: 0.950 AC: 144597 AN: 152150 Hom.: 69084 Cov.: 31

Gnomad AFR AF: 0.831

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.980

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.983

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 0.998

Gnomad OTH AF: 0.967

GnomAD2 exomes AF: 0.985 AC: 246683 AN: 250322 AF XY: 0.988

Gnomad AFR exome AF: 0.827

Gnomad AMR exome AF: 0.992

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.994

GnomAD4 exome AF: 0.994 AC: 1450619 AN: 1460064 Hom.: 721124 Cov.: 39 AF XY: 0.994 AC XY: 722014 AN XY: 726500

African (AFR) AF: 0.826 AC: 27611 AN: 33410

American (AMR) AF: 0.991 AC: 44335 AN: 44722

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26116 AN: 26116

East Asian (EAS) AF: 1.00 AC: 39691 AN: 39692

South Asian (SAS) AF: 0.986 AC: 85001 AN: 86210

European-Finnish (FIN) AF: 1.00 AC: 53414 AN: 53416

Middle Eastern (MID) AF: 0.989 AC: 5704 AN: 5768

European-Non Finnish (NFE) AF: 0.999 AC: 1109165 AN: 1110378

Other (OTH) AF: 0.987 AC: 59582 AN: 60352

GnomAD4 genome AF: 0.950 AC: 144704 AN: 152268 Hom.: 69132 Cov.: 31 AF XY: 0.953 AC XY: 70926 AN XY: 74448

African (AFR) AF: 0.831 AC: 34508 AN: 41516

American (AMR) AF: 0.980 AC: 14989 AN: 15294

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5184 AN: 5184

South Asian (SAS) AF: 0.984 AC: 4749 AN: 4828

European-Finnish (FIN) AF: 1.00 AC: 10611 AN: 10612

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 0.998 AC: 67939 AN: 68042

Other (OTH) AF: 0.968 AC: 2046 AN: 2114

Alfa AF: 0.963 Hom.: 68466

Bravo AF: 0.944

Asia WGS AF: 0.990 AC: 3442 AN: 3478

EpiCase AF: 0.999

EpiControl AF: 0.998

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	1.4
DANN	Benign	0.82
PhyloP100		-0.077
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Mutation Taster		=99/1	polymorphism (auto)

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: rs11071539; hg19: chr15-60789798; COSMIC: COSV108013122;