Genetic Variant RORA:c.167-27962T>G (chr15-60706648-A-C) – 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.167-27962T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.404 in 151,968 control chromosomes in the GnomAD database, including 12,708 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 0.40 ( 12708 hom., cov: 32)

Consequence

RORA
NM_134261.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.347

Publications

10 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, PanelApp Australia

RORA links:

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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=-0.72).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.454 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RORA	NM_134261.3	MANE Select	c.167-27962T>G		intron	N/A	NP_599023.1	P35398-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RORA	ENST00000335670.11	TSL:1 MANE Select	c.167-27962T>G	intron	N/A	ENSP00000335087.6	P35398-2
RORA	ENST00000551975.5	TSL:3	n.80-27962T>G	intron	N/A	ENSP00000449482.1	H0YII6
RORA	ENST00000557822.5	TSL:4	n.192-27962T>G	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.404

AC:

61332

AN:

151850

Hom.:

12690

Cov.:

show subpopulations

Gnomad AFR

AF:

0.460

Gnomad AMI

AF:

0.273

Gnomad AMR

AF:

0.406

Gnomad ASJ

AF:

0.420

Gnomad EAS

AF:

0.225

Gnomad SAS

AF:

0.443

Gnomad FIN

AF:

0.349

Gnomad MID

AF:

0.487

Gnomad NFE

AF:

0.389

Gnomad OTH

AF:

0.427

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

GnomAD4 genome

AF:

0.404

AC:

61403

AN:

151968

Hom.:

12708

Cov.:

AF XY:

0.401

AC XY:

29763

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.460

AC:

19029

AN:

41382

American (AMR)

AF:

0.407

AC:

6222

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.420

AC:

1456

AN:

3470

East Asian (EAS)

AF:

0.225

AC:

1167

AN:

5176

South Asian (SAS)

AF:

0.444

AC:

2136

AN:

4806

European-Finnish (FIN)

AF:

0.349

AC:

3693

AN:

10574

Middle Eastern (MID)

AF:

0.486

AC:

141

AN:

290

European-Non Finnish (NFE)

AF:

0.389

AC:

26410

AN:

67962

Other (OTH)

AF:

0.427

AC:

900

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1872

3744

5615

7487

9359

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

578

1156

1734

2312

2890

<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:

0.396

Hom.:

35451

Bravo

AF:

0.410

Asia WGS

AF:

0.364

AC:

1269

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

(source)

DANN

Benign

0.76

PhyloP100

0.35

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over