Genetic Variant RORA:c.166+80581G>A (chr15-61148472-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_134261.3(RORA):c.166+80581G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.48 in 151,982 control chromosomes in the GnomAD database, including 19,128 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 0.48 ( 19128 hom., cov: 31)

Consequence

RORA
NM_134261.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.874

Publications

12 publications found

Variant links:

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)

RORA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.97).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.587 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RORA	NM_134261.3 link	c.166+80581G>A		intron_variant	Intron 1 of 10	ENST00000335670.11	NP_599023.1	P35398-2
RORA	XM_047432928.1 link	c.-1752+80581G>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 link	c.166+80581G>A		intron_variant	Intron 1 of 10	1	NM_134261.3	ENSP00000335087.6		P35398-2

Frequencies

GnomAD3 genomes

AF:

0.481

AC:

72982

AN:

151864

Hom.:

19128

Cov.:

show subpopulations

Gnomad AFR

AF:

0.288

Gnomad AMI

AF:

0.766

Gnomad AMR

AF:

0.383

Gnomad ASJ

AF:

0.512

Gnomad EAS

AF:

0.439

Gnomad SAS

AF:

0.461

Gnomad FIN

AF:

0.654

Gnomad MID

AF:

0.513

Gnomad NFE

AF:

0.592

Gnomad OTH

AF:

0.456

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

GnomAD4 genome

AF:

0.480

AC:

72994

AN:

151982

Hom.:

19128

Cov.:

AF XY:

0.480

AC XY:

35634

AN XY:

74248

show subpopulations

African (AFR)

AF:

0.288

AC:

11922

AN:

41460

American (AMR)

AF:

0.383

AC:

5844

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.512

AC:

1776

AN:

3468

East Asian (EAS)

AF:

0.439

AC:

2262

AN:

5156

South Asian (SAS)

AF:

0.462

AC:

2230

AN:

4824

European-Finnish (FIN)

AF:

0.654

AC:

6903

AN:

10548

Middle Eastern (MID)

AF:

0.507

AC:

149

AN:

294

European-Non Finnish (NFE)

AF:

0.592

AC:

40236

AN:

67934

Other (OTH)

AF:

0.460

AC:

973

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1816

3631

5447

7262

9078

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

660

1320

1980

2640

3300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.402

Hom.:

1257

Bravo

AF:

0.451

Asia WGS

AF:

0.428

AC:

1488

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.34

(source)

DANN

Benign

0.54

PhyloP100

-0.87

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over