rs10869435

Variant names:

• chr9-74661165-T-A
• rs10869435
• NM_006914.4:c.759+427T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006914.4(RORB):​c.759+427T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.384 in 152,084 control chromosomes in the GnomAD database, including 12,281 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 0.38 (12281 hom., cov: 32)
• Consequence: RORB NM_006914.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.197
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.481 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.759+427T>A		intron	N/A	NP_008845.2
	RORB	NM_001365023.1		c.792+427T>A		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.759+427T>A		intron	N/A	ENSP00000366093.2	Q92753-1
	RORB	ENST00000396204.2	TSL:1	c.792+427T>A		intron	N/A	ENSP00000379507.2	Q92753-2

Frequencies

GnomAD3 genomes AF: 0.384 AC: 58383 AN: 151966 Hom.: 12270 Cov.: 32

Gnomad AFR AF: 0.202

Gnomad AMI AF: 0.589

Gnomad AMR AF: 0.387

Gnomad ASJ AF: 0.348

Gnomad EAS AF: 0.497

Gnomad SAS AF: 0.315

Gnomad FIN AF: 0.520

Gnomad MID AF: 0.437

Gnomad NFE AF: 0.468

Gnomad OTH AF: 0.398

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

GnomAD4 genome AF: 0.384 AC: 58424 AN: 152084 Hom.: 12281 Cov.: 32 AF XY: 0.388 AC XY: 28804 AN XY: 74316

African (AFR) AF: 0.202 AC: 8388 AN: 41502

American (AMR) AF: 0.388 AC: 5920 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.348 AC: 1208 AN: 3470

East Asian (EAS) AF: 0.497 AC: 2567 AN: 5168

South Asian (SAS) AF: 0.316 AC: 1522 AN: 4818

European-Finnish (FIN) AF: 0.520 AC: 5490 AN: 10548

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.468 AC: 31828 AN: 67988

Other (OTH) AF: 0.394 AC: 833 AN: 2114

Alfa AF: 0.429 Hom.: 1852

Bravo AF: 0.366

Asia WGS AF: 0.360 AC: 1253 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.7
DANN	Benign	0.46
PhyloP100		-0.20
Mutation Taster		=100/0	polymorphism (auto)

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: rs10869435; hg19: chr9-77276081;