15-60784392-A-G

Variant names:

• chr15-60784392-A-G
• rs877228
• NM_134261.3:c.167-105706T>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.167-105706T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.544 in 151,984 control chromosomes in the GnomAD database, including 22,804 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 0.54 (22804 hom., cov: 32)
• Consequence: RORA NM_134261.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.152
• Publications: 15 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=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.614 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.167-105706T>C		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.167-105706T>C		intron	N/A	ENSP00000335087.6
	RORA	ENST00000551975.5	TSL:3	n.80-105706T>C		intron	N/A	ENSP00000449482.1
	RORA	ENST00000557822.5	TSL:4	n.192-105706T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.544 AC: 82613 AN: 151866 Hom.: 22767 Cov.: 32

Gnomad AFR AF: 0.620

Gnomad AMI AF: 0.584

Gnomad AMR AF: 0.457

Gnomad ASJ AF: 0.506

Gnomad EAS AF: 0.413

Gnomad SAS AF: 0.524

Gnomad FIN AF: 0.516

Gnomad MID AF: 0.599

Gnomad NFE AF: 0.534

Gnomad OTH AF: 0.531

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

GnomAD4 genome AF: 0.544 AC: 82697 AN: 151984 Hom.: 22804 Cov.: 32 AF XY: 0.541 AC XY: 40161 AN XY: 74292

African (AFR) AF: 0.621 AC: 25726 AN: 41460

American (AMR) AF: 0.456 AC: 6965 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.506 AC: 1756 AN: 3472

East Asian (EAS) AF: 0.413 AC: 2128 AN: 5158

South Asian (SAS) AF: 0.525 AC: 2530 AN: 4818

European-Finnish (FIN) AF: 0.516 AC: 5444 AN: 10542

Middle Eastern (MID) AF: 0.586 AC: 171 AN: 292

European-Non Finnish (NFE) AF: 0.534 AC: 36317 AN: 67952

Other (OTH) AF: 0.535 AC: 1129 AN: 2110

Alfa AF: 0.534 Hom.: 45241

Bravo AF: 0.541

Asia WGS AF: 0.475 AC: 1650 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.3
DANN	Benign	0.52
PhyloP100		-0.15
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: rs877228; hg19: chr15-61076591;