NM_134261.3:c.166+22546G>A

Variant names:

• chr15-61206507-C-T
• rs34720147
• NM_134261.3:c.166+22546G>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.166+22546G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 152,030 control chromosomes in the GnomAD database, including 9,162 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 0.33 (9162 hom., cov: 32)
• Consequence: RORA NM_134261.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.53
• Publications: 4 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)

LOC105370841 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.403 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RORA	NM_134261.3	c.166+22546G>A		intron_variant	Intron 1 of 10	ENST00000335670.11	NP_599023.1
LOC105370841	XR_001751772.2	n.14487G>A		non_coding_transcript_exon_variant	Exon 3 of 3
LOC105370841	XR_007064661.1	n.14723G>A		non_coding_transcript_exon_variant	Exon 2 of 2
RORA	XM_047432928.1	c.-1752+22546G>A		intron_variant	Intron 1 of 10		XP_047288884.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RORA	ENST00000335670.11	c.166+22546G>A		intron_variant	Intron 1 of 10	1	NM_134261.3	ENSP00000335087.6

Frequencies

GnomAD3 genomes AF: 0.330 AC: 50063 AN: 151912 Hom.: 9157 Cov.: 32

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.550

Gnomad AMR AF: 0.310

Gnomad ASJ AF: 0.452

Gnomad EAS AF: 0.379

Gnomad SAS AF: 0.325

Gnomad FIN AF: 0.393

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.407

Gnomad OTH AF: 0.357

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

GnomAD4 genome AF: 0.329 AC: 50074 AN: 152030 Hom.: 9162 Cov.: 32 AF XY: 0.328 AC XY: 24341 AN XY: 74294

African (AFR) AF: 0.170 AC: 7064 AN: 41496

American (AMR) AF: 0.309 AC: 4722 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.452 AC: 1568 AN: 3470

East Asian (EAS) AF: 0.380 AC: 1957 AN: 5154

South Asian (SAS) AF: 0.326 AC: 1566 AN: 4808

European-Finnish (FIN) AF: 0.393 AC: 4155 AN: 10562

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.407 AC: 27672 AN: 67952

Other (OTH) AF: 0.359 AC: 759 AN: 2112

Alfa AF: 0.373 Hom.: 19293

Bravo AF: 0.319

Asia WGS AF: 0.333 AC: 1155 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.37
DANN	Benign	0.74
PhyloP100		-1.5
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: rs34720147; hg19: chr15-61498706;