15-60954476-T-C

Variant names:

• chr15-60954476-T-C
• rs17237514
• NM_134261.3:c.166+274577A>G

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+274577A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 150,504 control chromosomes in the GnomAD database, including 4,829 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 0.23 (4829 hom., cov: 30)
• Consequence: RORA NM_134261.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.275
• Publications: 3 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.596 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+274577A>G		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+274577A>G		intron	N/A	ENSP00000335087.6	P35398-2
	RORA	ENST00000551975.5	TSL:3	n.79+274577A>G		intron	N/A	ENSP00000449482.1	H0YII6
	RORA	ENST00000557822.5	TSL:4	n.191+274577A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.229 AC: 34451 AN: 150400 Hom.: 4813 Cov.: 30

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.0735

Gnomad AMR AF: 0.334

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.613

Gnomad SAS AF: 0.433

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.213

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.220

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

GnomAD4 genome AF: 0.229 AC: 34491 AN: 150504 Hom.: 4829 Cov.: 30 AF XY: 0.239 AC XY: 17545 AN XY: 73358

African (AFR) AF: 0.244 AC: 9997 AN: 40974

American (AMR) AF: 0.335 AC: 5072 AN: 15148

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 594 AN: 3462

East Asian (EAS) AF: 0.614 AC: 3144 AN: 5122

South Asian (SAS) AF: 0.432 AC: 2053 AN: 4754

European-Finnish (FIN) AF: 0.204 AC: 2071 AN: 10132

Middle Eastern (MID) AF: 0.213 AC: 61 AN: 286

European-Non Finnish (NFE) AF: 0.162 AC: 10963 AN: 67624

Other (OTH) AF: 0.224 AC: 469 AN: 2090

Alfa AF: 0.179 Hom.: 581

Bravo AF: 0.238

Asia WGS AF: 0.508 AC: 1765 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.8
DANN	Benign	0.75
PhyloP100		0.28
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: rs17237514; hg19: chr15-61246675;