Genetic Variant NM_006914.4:c.7+46366C>T (chr9-74544349-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_006914.4(RORB):c.7+46366C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.272 in 152,068 control chromosomes in the GnomAD database, including 5,854 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 0.27 ( 5854 hom., cov: 32)

Consequence

RORB
NM_006914.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0630

Publications

9 publications found

Variant links:

Genes affected

RORB (HGNC:10259): (RAR related orphan receptor B) The protein encoded by this gene is a member of the NR1 subfamily of nuclear hormone receptors. It is a DNA-binding protein that 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, and to help regulate the expression of some genes involved in circadian rhythm. [provided by RefSeq, Feb 2014]

RORB Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: ClinGen, Ambry Genetics
epilepsy, idiopathic generalized, susceptibility to, 15
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P

RORB links:

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new If you want to explore the variant's impact on the transcript NM_006914.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

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=-0.82).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.362 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006914.4. 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
	RORB	NM_006914.4	MANE Select	c.7+46366C>T		intron	N/A	NP_008845.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RORB	ENST00000376896.8	TSL:1 MANE Select	c.7+46366C>T		intron	N/A	ENSP00000366093.2	Q92753-1

Frequencies

GnomAD3 genomes

AF:

0.272

AC:

41340

AN:

151950

Hom.:

5847

Cov.:

show subpopulations

Gnomad AFR

AF:

0.277

Gnomad AMI

AF:

0.345

Gnomad AMR

AF:

0.370

Gnomad ASJ

AF:

0.252

Gnomad EAS

AF:

0.0782

Gnomad SAS

AF:

0.202

Gnomad FIN

AF:

0.195

Gnomad MID

AF:

0.351

Gnomad NFE

AF:

0.278

Gnomad OTH

AF:

0.289

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

GnomAD4 genome

AF:

0.272

AC:

41367

AN:

152068

Hom.:

5854

Cov.:

AF XY:

0.269

AC XY:

19983

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.277

AC:

11481

AN:

41472

American (AMR)

AF:

0.370

AC:

5656

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.252

AC:

875

AN:

3472

East Asian (EAS)

AF:

0.0788

AC:

408

AN:

5178

South Asian (SAS)

AF:

0.202

AC:

974

AN:

4816

European-Finnish (FIN)

AF:

0.195

AC:

2060

AN:

10568

Middle Eastern (MID)

AF:

0.347

AC:

102

AN:

294

European-Non Finnish (NFE)

AF:

0.278

AC:

18892

AN:

67982

Other (OTH)

AF:

0.287

AC:

606

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1516

3032

4548

6064

7580

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

416

832

1248

1664

2080

<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:

0.279

Hom.:

7875

Bravo

AF:

0.287

Asia WGS

AF:

0.161

AC:

562

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

2.9

(source)

DANN

Benign

0.59

PhyloP100

-0.063

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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