15-60756379-C-T

Variant names:

• chr15-60756379-C-T
• rs1020730
• NM_134261.3:c.167-77693G>A

Variant summary

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

The NM_134261.3(RORA):​c.167-77693G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 152,062 control chromosomes in the GnomAD database, including 3,742 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 0.20 (3742 hom., cov: 33)
• Consequence: RORA NM_134261.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.44
• 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.338 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RORA	NM_134261.3	c.167-77693G>A		intron_variant	Intron 1 of 10	ENST00000335670.11	NP_599023.1
RORA	XM_047432928.1	c.-1751-77693G>A		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.167-77693G>A		intron_variant	Intron 1 of 10	1	NM_134261.3	ENSP00000335087.6

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31081 AN: 151944 Hom.: 3743 Cov.: 33

Gnomad AFR AF: 0.342

Gnomad AMI AF: 0.131

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.224

Gnomad SAS AF: 0.250

Gnomad FIN AF: 0.170

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.181

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

GnomAD4 genome AF: 0.205 AC: 31114 AN: 152062 Hom.: 3742 Cov.: 33 AF XY: 0.204 AC XY: 15159 AN XY: 74322

African (AFR) AF: 0.342 AC: 14187 AN: 41450

American (AMR) AF: 0.133 AC: 2032 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 597 AN: 3470

East Asian (EAS) AF: 0.224 AC: 1156 AN: 5170

South Asian (SAS) AF: 0.249 AC: 1198 AN: 4816

European-Finnish (FIN) AF: 0.170 AC: 1791 AN: 10564

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.141 AC: 9585 AN: 67998

Other (OTH) AF: 0.183 AC: 386 AN: 2114

Alfa AF: 0.129 Hom.: 297

Bravo AF: 0.203

Asia WGS AF: 0.254 AC: 881 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.13
DANN	Benign	0.79
PhyloP100		-1.4
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: rs1020730; hg19: chr15-61048578;