15-60977046-C-A

Variant names:

• chr15-60977046-C-A
• rs2414687
• NM_134261.3:c.166+252007G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_134261.3(RORA):​c.166+252007G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.263 in 148,620 control chromosomes in the GnomAD database, including 5,459 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.26 (5459 hom., cov: 30)
• Consequence: RORA NM_134261.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.785
• Publications: 8 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 Gene-Disease associations (from GenCC):

• intellectual developmental disorder with or without epilepsy or cerebellar ataxia

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.324 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RORA	NM_134261.3	c.166+252007G>T		intron_variant	Intron 1 of 10	ENST00000335670.11	NP_599023.1
RORA	XM_047432928.1	c.-1752+252007G>T		intron_variant	Intron 1 of 10		XP_047288884.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RORA	ENST00000335670.11	c.166+252007G>T		intron_variant	Intron 1 of 10	1	NM_134261.3	ENSP00000335087.6

Frequencies

GnomAD3 genomes AF: 0.263 AC: 39113 AN: 148532 Hom.: 5457 Cov.: 30

Gnomad AFR AF: 0.329

Gnomad AMI AF: 0.274

Gnomad AMR AF: 0.243

Gnomad ASJ AF: 0.239

Gnomad EAS AF: 0.0591

Gnomad SAS AF: 0.179

Gnomad FIN AF: 0.173

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.251

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.263 AC: 39129 AN: 148620 Hom.: 5459 Cov.: 30 AF XY: 0.257 AC XY: 18571 AN XY: 72216

African (AFR) AF: 0.329 AC: 13301 AN: 40414

American (AMR) AF: 0.243 AC: 3605 AN: 14834

Ashkenazi Jewish (ASJ) AF: 0.239 AC: 821 AN: 3442

East Asian (EAS) AF: 0.0590 AC: 283 AN: 4794

South Asian (SAS) AF: 0.179 AC: 840 AN: 4690

European-Finnish (FIN) AF: 0.173 AC: 1665 AN: 9628

Middle Eastern (MID) AF: 0.240 AC: 69 AN: 288

European-Non Finnish (NFE) AF: 0.263 AC: 17783 AN: 67556

Other (OTH) AF: 0.249 AC: 514 AN: 2068

Alfa AF: 0.235 Hom.: 2379

Bravo AF: 0.268

Asia WGS AF: 0.128 AC: 444 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.034
DANN	Benign	0.43
PhyloP100		-0.79
Mutation Taster		=100/0	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: rs2414687; hg19: chr15-61269245;