Genetic Variant NM_134261.3:c.166+42846T>A (chr15-61186207-A-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+42846T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.34 in 152,094 control chromosomes in the GnomAD database, including 10,993 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 0.34 ( 10993 hom., cov: 31)

Consequence

RORA
NM_134261.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.96

Publications

3 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:

LOC105370841 (HGNC:):

LOC105370841 links:

ENSG00000259481 (HGNC:51412):

ENSG00000259481 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=-0.92).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.454 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
RORA	NM_134261.3 link	c.166+42846T>A	intron_variant	Intron 1 of 10	ENST00000335670.11	NP_599023.1	P35398-2
LOC105370841	XR_001751772.2 link	n.34787T>A	non_coding_transcript_exon_variant	Exon 3 of 3
LOC105370841	XR_007064661.1 link	n.35023T>A	non_coding_transcript_exon_variant	Exon 2 of 2
RORA	XM_047432928.1 link	c.-1752+42846T>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+42846T>A		intron_variant	Intron 1 of 10	1	NM_134261.3	ENSP00000335087.6		P35398-2

Frequencies

GnomAD3 genomes

AF:

0.340

AC:

51688

AN:

151976

Hom.:

10992

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0834

Gnomad AMI

AF:

0.556

Gnomad AMR

AF:

0.319

Gnomad ASJ

AF:

0.473

Gnomad EAS

AF:

0.469

Gnomad SAS

AF:

0.330

Gnomad FIN

AF:

0.500

Gnomad MID

AF:

0.367

Gnomad NFE

AF:

0.457

Gnomad OTH

AF:

0.360

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

GnomAD4 genome

AF:

0.340

AC:

51686

AN:

152094

Hom.:

10993

Cov.:

AF XY:

0.340

AC XY:

25267

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.0832

AC:

3455

AN:

41530

American (AMR)

AF:

0.319

AC:

4873

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.473

AC:

1639

AN:

3468

East Asian (EAS)

AF:

0.469

AC:

2422

AN:

5162

South Asian (SAS)

AF:

0.332

AC:

1592

AN:

4802

European-Finnish (FIN)

AF:

0.500

AC:

5287

AN:

10566

Middle Eastern (MID)

AF:

0.357

AC:

105

AN:

294

European-Non Finnish (NFE)

AF:

0.457

AC:

31040

AN:

67966

Other (OTH)

AF:

0.364

AC:

767

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1522

3044

4566

6088

7610

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

514

1028

1542

2056

2570

<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:

0.392

Hom.:

1821

Bravo

AF:

0.319

Asia WGS

AF:

0.369

AC:

1283

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.34

(source)

DANN

Benign

0.36

PhyloP100

-2.0

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