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

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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RORA	NM_134261.3	c.1428C>A	p.Thr476Thr	synonymous_variant	Exon 11 of 11	ENST00000335670.11	NP_599023.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RORA	ENST00000335670.11	c.1428C>A	p.Thr476Thr	synonymous_variant	Exon 11 of 11	1	NM_134261.3	ENSP00000335087.6

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

Gnomad4 AFR exome AF: 0.826 AC: 27611 AN: 33410

Gnomad4 AMR exome AF: 0.991 AC: 44335 AN: 44722

Gnomad4 ASJ exome AF: 1.00 AC: 26116 AN: 26116

Gnomad4 EAS exome AF: 1.00 AC: 39691 AN: 39692

Gnomad4 SAS exome AF: 0.986 AC: 85001 AN: 86210

Gnomad4 FIN exome AF: 1.00 AC: 53414 AN: 53416

Gnomad4 NFE exome AF: 0.999 AC: 1109165 AN: 1110378

Gnomad4 Remaining exome 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

Gnomad4 AFR AF: 0.831 AC: 0.831198 AN: 0.831198

Gnomad4 AMR AF: 0.980 AC: 0.980058 AN: 0.980058

Gnomad4 ASJ AF: 1.00 AC: 1 AN: 1

Gnomad4 EAS AF: 1.00 AC: 1 AN: 1

Gnomad4 SAS AF: 0.984 AC: 0.983637 AN: 0.983637

Gnomad4 FIN AF: 1.00 AC: 0.999906 AN: 0.999906

Gnomad4 NFE AF: 0.998 AC: 0.998486 AN: 0.998486

Gnomad4 OTH AF: 0.968 AC: 0.967833 AN: 0.967833

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual developmental disorder with or without epilepsy or cerebellar ataxia Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	1.4
DANN	Benign	0.82
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

Publications

LitVar

Other links and lift over

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