15-61154154-T-G

Variant names:

• chr15-61154154-T-G
• rs8034864
• NM_134261.3:c.166+74899A>C

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+74899A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.71 in 151,918 control chromosomes in the GnomAD database, including 39,207 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 0.71 (39207 hom., cov: 31)
• Consequence: RORA NM_134261.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.923
• Publications: 6 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.782 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RORA	NM_134261.3	c.166+74899A>C		intron_variant	Intron 1 of 10	ENST00000335670.11	NP_599023.1
RORA	XM_047432928.1	c.-1752+74899A>C		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+74899A>C		intron_variant	Intron 1 of 10	1	NM_134261.3	ENSP00000335087.6

Frequencies

GnomAD3 genomes AF: 0.710 AC: 107813 AN: 151800 Hom.: 39179 Cov.: 31

Gnomad AFR AF: 0.671

Gnomad AMI AF: 0.883

Gnomad AMR AF: 0.552

Gnomad ASJ AF: 0.744

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.536

Gnomad FIN AF: 0.791

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.787

Gnomad OTH AF: 0.687

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

GnomAD4 genome AF: 0.710 AC: 107884 AN: 151918 Hom.: 39207 Cov.: 31 AF XY: 0.702 AC XY: 52132 AN XY: 74232

African (AFR) AF: 0.671 AC: 27778 AN: 41412

American (AMR) AF: 0.551 AC: 8420 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.744 AC: 2582 AN: 3470

East Asian (EAS) AF: 0.431 AC: 2216 AN: 5146

South Asian (SAS) AF: 0.538 AC: 2586 AN: 4810

European-Finnish (FIN) AF: 0.791 AC: 8339 AN: 10546

Middle Eastern (MID) AF: 0.694 AC: 204 AN: 294

European-Non Finnish (NFE) AF: 0.787 AC: 53499 AN: 67942

Other (OTH) AF: 0.688 AC: 1455 AN: 2114

Alfa AF: 0.743 Hom.: 22902

Bravo AF: 0.693

Asia WGS AF: 0.477 AC: 1660 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.58
DANN	Benign	0.63
PhyloP100		-0.92
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: rs8034864; hg19: chr15-61446353;