rs4774388

Variant names:

• chr15-61174799-C-T
• rs4774388
• NM_134261.3:c.166+54254G>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.166+54254G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.803 in 152,030 control chromosomes in the GnomAD database, including 49,415 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 0.80 (49415 hom., cov: 31)
• Consequence: RORA NM_134261.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.211
• Publications: 27 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, PanelApp Australia

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.849 is higher than 0.05.

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.166+54254G>A		intron	N/A	NP_599023.1	P35398-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RORA	ENST00000335670.11	TSL:1 MANE Select	c.166+54254G>A		intron	N/A	ENSP00000335087.6	P35398-2
	RORA	ENST00000551975.5	TSL:3	n.79+54254G>A		intron	N/A	ENSP00000449482.1	H0YII6
	RORA	ENST00000557822.5	TSL:4	n.191+54254G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.803 AC: 121959 AN: 151912 Hom.: 49390 Cov.: 31

Gnomad AFR AF: 0.774

Gnomad AMI AF: 0.950

Gnomad AMR AF: 0.713

Gnomad ASJ AF: 0.880

Gnomad EAS AF: 0.599

Gnomad SAS AF: 0.628

Gnomad FIN AF: 0.849

Gnomad MID AF: 0.828

Gnomad NFE AF: 0.855

Gnomad OTH AF: 0.801

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

GnomAD4 genome AF: 0.803 AC: 122029 AN: 152030 Hom.: 49415 Cov.: 31 AF XY: 0.796 AC XY: 59177 AN XY: 74302

African (AFR) AF: 0.774 AC: 32099 AN: 41468

American (AMR) AF: 0.712 AC: 10875 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.880 AC: 3052 AN: 3470

East Asian (EAS) AF: 0.599 AC: 3073 AN: 5130

South Asian (SAS) AF: 0.627 AC: 3015 AN: 4806

European-Finnish (FIN) AF: 0.849 AC: 8978 AN: 10576

Middle Eastern (MID) AF: 0.815 AC: 238 AN: 292

European-Non Finnish (NFE) AF: 0.855 AC: 58141 AN: 67994

Other (OTH) AF: 0.801 AC: 1692 AN: 2112

Alfa AF: 0.830 Hom.: 235524

Bravo AF: 0.793

Asia WGS AF: 0.647 AC: 2249 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.94
DANN	Benign	0.51
PhyloP100		-0.21
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: rs4774388; hg19: chr15-61466998;