15-60778145-C-G

Variant names:

• chr15-60778145-C-G
• rs922781
• NM_134261.3:c.167-99459G>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.167-99459G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.588 in 152,006 control chromosomes in the GnomAD database, including 26,737 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 0.59 (26737 hom., cov: 32)
• Consequence: RORA NM_134261.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.277
• Publications: 7 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.736 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.167-99459G>C		intron	N/A	NP_599023.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RORA	ENST00000335670.11	TSL:1 MANE Select	c.167-99459G>C		intron	N/A	ENSP00000335087.6
	RORA	ENST00000551975.5	TSL:3	n.80-99459G>C		intron	N/A	ENSP00000449482.1
	RORA	ENST00000557822.5	TSL:4	n.192-99459G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.588 AC: 89361 AN: 151888 Hom.: 26719 Cov.: 32

Gnomad AFR AF: 0.674

Gnomad AMI AF: 0.507

Gnomad AMR AF: 0.562

Gnomad ASJ AF: 0.570

Gnomad EAS AF: 0.755

Gnomad SAS AF: 0.660

Gnomad FIN AF: 0.600

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.525

Gnomad OTH AF: 0.577

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

GnomAD4 genome AF: 0.588 AC: 89419 AN: 152006 Hom.: 26737 Cov.: 32 AF XY: 0.592 AC XY: 43987 AN XY: 74306

African (AFR) AF: 0.673 AC: 27897 AN: 41426

American (AMR) AF: 0.562 AC: 8584 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.570 AC: 1978 AN: 3470

East Asian (EAS) AF: 0.756 AC: 3909 AN: 5170

South Asian (SAS) AF: 0.659 AC: 3175 AN: 4820

European-Finnish (FIN) AF: 0.600 AC: 6337 AN: 10556

Middle Eastern (MID) AF: 0.636 AC: 187 AN: 294

European-Non Finnish (NFE) AF: 0.525 AC: 35680 AN: 67974

Other (OTH) AF: 0.573 AC: 1211 AN: 2112

Alfa AF: 0.414 Hom.: 1053

Bravo AF: 0.587

Asia WGS AF: 0.702 AC: 2437 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	3.1
DANN	Benign	0.44
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: rs922781; hg19: chr15-61070344;