15-60499904-T-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_134261.3(RORA):c.1395A>T(p.Gly465=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,600,684 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00098 (11 hom.)
• Consequence: RORA NM_134261.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.186

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

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 15-60499904-T-A is Benign according to our data. Variant chr15-60499904-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 1675578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.186 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000977 (1415/1448426) while in subpopulation MID AF= 0.0225 (129/5722). AF 95% confidence interval is 0.0194. There are 11 homozygotes in gnomad4_exome. There are 762 alleles in male gnomad4_exome subpopulation. Median coverage is 27. This position pass quality control queck.
• BS2: High AC in GnomAd at 211 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RORA	NM_134261.3	c.1395A>T	p.Gly465=	synonymous_variant	10/11	ENST00000335670.11
RORA-AS1	NR_120342.1	n.290-10504T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RORA	ENST00000335670.11	c.1395A>T	p.Gly465=	synonymous_variant	10/11	1	NM_134261.3
RORA-AS1	ENST00000559824.5	n.290-10504T>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 211 AN: 152140 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.000911

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00135 AC: 336 AN: 248492 Hom.: 3 AF XY: 0.00151 AC XY: 203 AN XY: 134492

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.00237

Gnomad ASJ exome AF: 0.00865

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00112

Gnomad FIN exome AF: 0.0000934

Gnomad NFE exome AF: 0.00105

Gnomad OTH exome AF: 0.00233

GnomAD4 exome AF: 0.000977 AC: 1415 AN: 1448426 Hom.: 11 Cov.: 27 AF XY: 0.00106 AC XY: 762 AN XY: 721554

Gnomad4 AFR exome AF: 0.000576

Gnomad4 AMR exome AF: 0.00245

Gnomad4 ASJ exome AF: 0.0114

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00112

Gnomad4 FIN exome AF: 0.0000941

Gnomad4 NFE exome AF: 0.000604

Gnomad4 OTH exome AF: 0.00164

GnomAD4 genome AF: 0.00139 AC: 211 AN: 152258 Hom.: 1 Cov.: 32 AF XY: 0.00145 AC XY: 108 AN XY: 74444

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00550

Gnomad4 ASJ AF: 0.0109

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000911

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00163 Hom.: 0

Bravo AF: 0.00151

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00219

EpiControl AF: 0.00208

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

RORA-AS1: BS2 -

RORA-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 19, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
Cadd	Benign	5.5
Dann	Benign	0.80

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: rs117458658; hg19: chr15-60792103;