rs339998

Variant names:

• chr15-60655564-C-T
• rs339998
• NM_134261.3:c.196+23093G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_134261.3(RORA):​c.196+23093G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 151,958 control chromosomes in the GnomAD database, including 11,451 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 0.38 (11451 hom., cov: 32)
• Consequence: RORA NM_134261.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.19
• 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)

LOC105370846 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RORA	NM_134261.3	c.196+23093G>A		intron_variant	Intron 2 of 10	ENST00000335670.11	NP_599023.1
LOC105370846	XR_007064663.1	n.8302C>T		non_coding_transcript_exon_variant	Exon 5 of 5
RORA	XM_011521875.3	c.139+23093G>A		intron_variant	Intron 2 of 10		XP_011520177.1
RORA	XM_047432928.1	c.-216+21587G>A		intron_variant	Intron 2 of 10		XP_047288884.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RORA	ENST00000335670.11	c.196+23093G>A		intron_variant	Intron 2 of 10	1	NM_134261.3	ENSP00000335087.6

Frequencies

GnomAD3 genomes AF: 0.385 AC: 58456 AN: 151840 Hom.: 11447 Cov.: 32

Gnomad AFR AF: 0.325

Gnomad AMI AF: 0.340

Gnomad AMR AF: 0.421

Gnomad ASJ AF: 0.446

Gnomad EAS AF: 0.397

Gnomad SAS AF: 0.484

Gnomad FIN AF: 0.364

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.405

Gnomad OTH AF: 0.415

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

GnomAD4 genome AF: 0.385 AC: 58491 AN: 151958 Hom.: 11451 Cov.: 32 AF XY: 0.386 AC XY: 28653 AN XY: 74272

African (AFR) AF: 0.325 AC: 13460 AN: 41412

American (AMR) AF: 0.420 AC: 6415 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.446 AC: 1549 AN: 3470

East Asian (EAS) AF: 0.397 AC: 2054 AN: 5170

South Asian (SAS) AF: 0.482 AC: 2323 AN: 4816

European-Finnish (FIN) AF: 0.364 AC: 3838 AN: 10550

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.405 AC: 27533 AN: 67960

Other (OTH) AF: 0.415 AC: 877 AN: 2114

Alfa AF: 0.408 Hom.: 21655

Bravo AF: 0.387

Asia WGS AF: 0.440 AC: 1528 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.020
DANN	Benign	0.37
PhyloP100		-2.2
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: rs339998; hg19: chr15-60947763;