9-74632681-A-G

Variant names:

• chr9-74632681-A-G
• rs7032677
• NM_006914.4:c.94-1950A>G

Variant summary

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

The NM_006914.4(RORB):​c.94-1950A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.448 in 151,956 control chromosomes in the GnomAD database, including 16,816 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 0.45 (16816 hom., cov: 32)
• Consequence: RORB NM_006914.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.51
• Publications: 8 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

ENSG00000286944 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.753 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RORB	NM_006914.4	c.94-1950A>G		intron_variant	Intron 2 of 9	ENST00000376896.8	NP_008845.2
RORB	NM_001365023.1	c.127-1950A>G		intron_variant	Intron 2 of 9		NP_001351952.1
LOC105376088	XR_929948.3	n.179+188T>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RORB	ENST00000376896.8	c.94-1950A>G		intron_variant	Intron 2 of 9	1	NM_006914.4	ENSP00000366093.2
RORB	ENST00000396204.2	c.127-1950A>G		intron_variant	Intron 2 of 9	1		ENSP00000379507.2
ENSG00000286944	ENST00000658390.1	n.3120+188T>C		intron_variant	Intron 2 of 3

Frequencies

GnomAD3 genomes AF: 0.449 AC: 68147 AN: 151838 Hom.: 16833 Cov.: 32

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.400

Gnomad AMR AF: 0.464

Gnomad ASJ AF: 0.590

Gnomad EAS AF: 0.772

Gnomad SAS AF: 0.498

Gnomad FIN AF: 0.582

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.518

Gnomad OTH AF: 0.476

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

GnomAD4 genome AF: 0.448 AC: 68129 AN: 151956 Hom.: 16816 Cov.: 32 AF XY: 0.453 AC XY: 33684 AN XY: 74282

African (AFR) AF: 0.237 AC: 9813 AN: 41472

American (AMR) AF: 0.464 AC: 7081 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.590 AC: 2048 AN: 3470

East Asian (EAS) AF: 0.773 AC: 3994 AN: 5170

South Asian (SAS) AF: 0.497 AC: 2396 AN: 4824

European-Finnish (FIN) AF: 0.582 AC: 6143 AN: 10550

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.518 AC: 35143 AN: 67906

Other (OTH) AF: 0.472 AC: 995 AN: 2106

Alfa AF: 0.494 Hom.: 61621

Bravo AF: 0.432

Asia WGS AF: 0.554 AC: 1924 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	16
DANN	Benign	0.67
PhyloP100		1.5
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: rs7032677; hg19: chr9-77247597; COSMIC: COSV65334351;