NM_134261.3:c.167-12544C>T

Variant names:

• chr15-60691230-G-A
• rs880626
• NM_134261.3:c.167-12544C>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.167-12544C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.303 in 151,900 control chromosomes in the GnomAD database, including 7,606 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 0.30 (7606 hom., cov: 32)
• Consequence: RORA NM_134261.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0600
• Publications: 12 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=-0.99).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.481 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RORA	NM_134261.3	c.167-12544C>T		intron_variant	Intron 1 of 10	ENST00000335670.11	NP_599023.1
RORA	XM_011521875.3	c.110-12544C>T		intron_variant	Intron 1 of 10		XP_011520177.1
RORA	XM_047432928.1	c.-1751-12544C>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.167-12544C>T		intron_variant	Intron 1 of 10	1	NM_134261.3	ENSP00000335087.6

Frequencies

GnomAD3 genomes AF: 0.303 AC: 45955 AN: 151782 Hom.: 7597 Cov.: 32

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.239

Gnomad AMR AF: 0.471

Gnomad ASJ AF: 0.376

Gnomad EAS AF: 0.497

Gnomad SAS AF: 0.481

Gnomad FIN AF: 0.310

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.268

Gnomad OTH AF: 0.330

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

GnomAD4 genome AF: 0.303 AC: 45995 AN: 151900 Hom.: 7606 Cov.: 32 AF XY: 0.312 AC XY: 23187 AN XY: 74234

African (AFR) AF: 0.244 AC: 10093 AN: 41410

American (AMR) AF: 0.471 AC: 7194 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.376 AC: 1305 AN: 3470

East Asian (EAS) AF: 0.497 AC: 2575 AN: 5176

South Asian (SAS) AF: 0.482 AC: 2315 AN: 4804

European-Finnish (FIN) AF: 0.310 AC: 3269 AN: 10534

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.268 AC: 18226 AN: 67938

Other (OTH) AF: 0.332 AC: 700 AN: 2108

Alfa AF: 0.287 Hom.: 11517

Bravo AF: 0.314

Asia WGS AF: 0.467 AC: 1622 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	2.4
DANN	Benign	0.53
PhyloP100		0.060
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: rs880626; hg19: chr15-60983429;