15-60645203-C-T

Variant names:

• chr15-60645203-C-T
• rs339978
• NM_134261.3:c.196+33454G>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+33454G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0682 in 150,610 control chromosomes in the GnomAD database, including 871 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 0.068 (871 hom., cov: 32)
• Consequence: RORA NM_134261.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.365
• 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)

ENSG00000287508 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.199 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RORA	NM_134261.3	c.196+33454G>A		intron_variant	Intron 2 of 10	ENST00000335670.11	NP_599023.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RORA	ENST00000335670.11	c.196+33454G>A		intron_variant	Intron 2 of 10	1	NM_134261.3	ENSP00000335087.6

Frequencies

GnomAD3 genomes AF: 0.0678 AC: 10206 AN: 150492 Hom.: 854 Cov.: 32

Gnomad AFR AF: 0.202

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.0352

Gnomad ASJ AF: 0.0142

Gnomad EAS AF: 0.0174

Gnomad SAS AF: 0.0163

Gnomad FIN AF: 0.00536

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0155

Gnomad OTH AF: 0.0556

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

GnomAD4 genome AF: 0.0682 AC: 10270 AN: 150610 Hom.: 871 Cov.: 32 AF XY: 0.0654 AC XY: 4806 AN XY: 73452

African (AFR) AF: 0.203 AC: 8296 AN: 40888

American (AMR) AF: 0.0351 AC: 529 AN: 15088

Ashkenazi Jewish (ASJ) AF: 0.0142 AC: 49 AN: 3460

East Asian (EAS) AF: 0.0174 AC: 89 AN: 5112

South Asian (SAS) AF: 0.0164 AC: 78 AN: 4770

European-Finnish (FIN) AF: 0.00536 AC: 55 AN: 10264

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0155 AC: 1051 AN: 67732

Other (OTH) AF: 0.0554 AC: 116 AN: 2092

Alfa AF: 0.0389 Hom.: 656

Bravo AF: 0.0755

Asia WGS AF: 0.0540 AC: 189 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.66
DANN	Benign	0.54
PhyloP100		-0.36
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: rs339978; hg19: chr15-60937402;