chr15-60499904-T-A

Variant names:

• chr15-60499904-T-A
• rs117458658
• NM_134261.3:c.1395A>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_134261.3(RORA):​c.1395A>T​(p.Gly465Gly) 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:3
• Conservation: PhyloP100: -0.186
• Publications: 3 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 -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 VariationId 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. GnomAdExome4 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 GnomAdExome4. There are 762 alleles in the male GnomAdExome4 subpopulation. Median coverage is 27. This position passed quality control check.
• BS2: High AC in GnomAd4 at 211 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.1395A>T	p.Gly465Gly	synonymous	Exon 10 of 11	NP_599023.1	P35398-2
	RORA	NM_134260.3		c.1494A>T	p.Gly498Gly	synonymous	Exon 11 of 12	NP_599022.1	P35398-1
	RORA	NM_002943.4		c.1470A>T	p.Gly490Gly	synonymous	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.1395A>T	p.Gly465Gly	synonymous	Exon 10 of 11	ENSP00000335087.6	P35398-2
	RORA	ENST00000261523.9	TSL:1	c.1494A>T	p.Gly498Gly	synonymous	Exon 11 of 12	ENSP00000261523.5	P35398-1
	RORA	ENST00000309157.8	TSL:1	c.1470A>T	p.Gly490Gly	synonymous	Exon 10 of 11	ENSP00000309753.3	A0A0C4DFP5

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

GnomAD2 exomes AF: 0.00135 AC: 336 AN: 248492 AF XY: 0.00151

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 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

African (AFR) AF: 0.000576 AC: 19 AN: 32964

American (AMR) AF: 0.00245 AC: 108 AN: 44078

Ashkenazi Jewish (ASJ) AF: 0.0114 AC: 295 AN: 25916

East Asian (EAS) AF: 0.00 AC: 0 AN: 39594

South Asian (SAS) AF: 0.00112 AC: 96 AN: 85820

European-Finnish (FIN) AF: 0.0000941 AC: 5 AN: 53146

Middle Eastern (MID) AF: 0.0225 AC: 129 AN: 5722

European-Non Finnish (NFE) AF: 0.000604 AC: 665 AN: 1101308

Other (OTH) AF: 0.00164 AC: 98 AN: 59878

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

African (AFR) AF: 0.000144 AC: 6 AN: 41554

American (AMR) AF: 0.00550 AC: 84 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0109 AC: 38 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4814

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.000911 AC: 62 AN: 68020

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

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

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	RORA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	5.5
DANN	Benign	0.80
PhyloP100		-0.19
Mutation Taster		=100/0	polymorphism

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: rs117458658; hg19: chr15-60792103;