rs17691363

Variant names:

• chr9-74617578-A-G
• rs17691363
• NM_006914.4:c.8-12704A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BS1 BS2

The NM_006914.4(RORB):​c.8-12704A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0302 in 152,246 control chromosomes in the GnomAD database, including 106 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 0.030 (106 hom., cov: 32)
• Consequence: RORB NM_006914.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.69
• Publications: 7 publications found

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: Ambry Genetics, ClinGen
• epilepsy, idiopathic generalized, susceptibility to, 15

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0302 (4593/152246) while in subpopulation NFE AF = 0.0477 (3246/68012). AF 95% confidence interval is 0.0464. There are 106 homozygotes in GnomAd4. There are 2190 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4593 AD gene.

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.8-12704A>G		intron	N/A	NP_008845.2
	RORB	NM_001365023.1		c.40+1939A>G		intron	N/A	NP_001351952.1	Q92753-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RORB	ENST00000376896.8	TSL:1 MANE Select	c.8-12704A>G		intron	N/A	ENSP00000366093.2	Q92753-1
	RORB	ENST00000396204.2	TSL:1	c.40+1939A>G		intron	N/A	ENSP00000379507.2	Q92753-2

Frequencies

GnomAD3 genomes AF: 0.0302 AC: 4600 AN: 152128 Hom.: 108 Cov.: 32

Gnomad AFR AF: 0.00734

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0188

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0209

Gnomad FIN AF: 0.0502

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0478

Gnomad OTH AF: 0.0220

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

GnomAD4 genome AF: 0.0302 AC: 4593 AN: 152246 Hom.: 106 Cov.: 32 AF XY: 0.0294 AC XY: 2190 AN XY: 74438

African (AFR) AF: 0.00732 AC: 304 AN: 41556

American (AMR) AF: 0.0187 AC: 286 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0173 AC: 60 AN: 3472

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5182

South Asian (SAS) AF: 0.0201 AC: 97 AN: 4826

European-Finnish (FIN) AF: 0.0502 AC: 532 AN: 10600

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0477 AC: 3246 AN: 68012

Other (OTH) AF: 0.0217 AC: 46 AN: 2116

Alfa AF: 0.0408 Hom.: 254

Bravo AF: 0.0272

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	17
DANN	Benign	0.73
PhyloP100		1.7
Mutation Taster		=100/0	polymorphism

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: rs17691363; hg19: chr9-77232494;