chr15-61203259-G-A

Variant names:

• chr15-61203259-G-A
• rs726914
• NM_134261.3:c.166+25794C>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+25794C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 152,084 control chromosomes in the GnomAD database, including 6,600 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 0.27 (6600 hom., cov: 32)
• Consequence: RORA NM_134261.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.441
• Publications: 5 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)

LOC105370841 (HGNC:):

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 (EAS) allele frequency at 95% confidence interval = 0.359 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RORA	NM_134261.3	MANE Select	c.166+25794C>T		intron	N/A	NP_599023.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RORA	ENST00000335670.11	TSL:1 MANE Select	c.166+25794C>T		intron	N/A	ENSP00000335087.6
	RORA	ENST00000558904.2	TSL:2	c.103+25794C>T		intron	N/A	ENSP00000484955.1
	RORA	ENST00000551975.5	TSL:3	n.79+25794C>T		intron	N/A	ENSP00000449482.1

Frequencies

GnomAD3 genomes AF: 0.269 AC: 40928 AN: 151964 Hom.: 6598 Cov.: 32

Gnomad AFR AF: 0.0931

Gnomad AMI AF: 0.504

Gnomad AMR AF: 0.261

Gnomad ASJ AF: 0.380

Gnomad EAS AF: 0.374

Gnomad SAS AF: 0.329

Gnomad FIN AF: 0.328

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.348

Gnomad OTH AF: 0.280

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

GnomAD4 genome AF: 0.269 AC: 40925 AN: 152084 Hom.: 6600 Cov.: 32 AF XY: 0.269 AC XY: 19965 AN XY: 74326

African (AFR) AF: 0.0928 AC: 3856 AN: 41536

American (AMR) AF: 0.261 AC: 3987 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.380 AC: 1319 AN: 3468

East Asian (EAS) AF: 0.373 AC: 1926 AN: 5160

South Asian (SAS) AF: 0.329 AC: 1584 AN: 4808

European-Finnish (FIN) AF: 0.328 AC: 3463 AN: 10550

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.348 AC: 23639 AN: 67968

Other (OTH) AF: 0.283 AC: 597 AN: 2112

Alfa AF: 0.321 Hom.: 25877

Bravo AF: 0.258

Asia WGS AF: 0.322 AC: 1117 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	1.5
DANN	Benign	0.34
PhyloP100		0.44
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: rs726914; hg19: chr15-61495458; COSMIC: COSV59530599;