rs3903529

Variant names:

• chr9-74649312-T-A
• rs3903529
• NM_006914.4:c.637+6497T>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.637+6497T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 151,918 control chromosomes in the GnomAD database, including 4,109 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 0.23 (4109 hom., cov: 31)
• Consequence: RORB NM_006914.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.07
• Publications: 17 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):

• epilepsy, idiopathic generalized, susceptibility to, 15

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• complex neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• epilepsy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RORB	NM_006914.4	c.637+6497T>A		intron_variant	Intron 4 of 9	ENST00000376896.8	NP_008845.2
RORB	NM_001365023.1	c.670+6497T>A		intron_variant	Intron 4 of 9		NP_001351952.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RORB	ENST00000376896.8	c.637+6497T>A		intron_variant	Intron 4 of 9	1	NM_006914.4	ENSP00000366093.2
RORB	ENST00000396204.2	c.670+6497T>A		intron_variant	Intron 4 of 9	1		ENSP00000379507.2

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34246 AN: 151800 Hom.: 4102 Cov.: 31

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.267

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.285

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.229

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

GnomAD4 genome AF: 0.226 AC: 34281 AN: 151918 Hom.: 4109 Cov.: 31 AF XY: 0.228 AC XY: 16943 AN XY: 74260

African (AFR) AF: 0.148 AC: 6113 AN: 41422

American (AMR) AF: 0.267 AC: 4080 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 493 AN: 3470

East Asian (EAS) AF: 0.116 AC: 599 AN: 5158

South Asian (SAS) AF: 0.186 AC: 896 AN: 4808

European-Finnish (FIN) AF: 0.285 AC: 3007 AN: 10560

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.270 AC: 18344 AN: 67932

Other (OTH) AF: 0.228 AC: 480 AN: 2104

Alfa AF: 0.247 Hom.: 609

Bravo AF: 0.220

Asia WGS AF: 0.151 AC: 524 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.32
DANN	Benign	0.77
PhyloP100		-1.1
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: rs3903529; hg19: chr9-77264228;