9-74634466-C-T

Variant names:

• chr9-74634466-C-T
• rs3750420
• NM_006914.4:c.94-165C>T

Variant summary

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

The NM_006914.4(RORB):​c.94-165C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 152,108 control chromosomes in the GnomAD database, including 7,125 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 0.30 (7125 hom., cov: 33)
• Consequence: RORB NM_006914.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.570
• Publications: 24 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

ENSG00000286944 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.54 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.94-165C>T		intron	N/A	NP_008845.2
	RORB	NM_001365023.1		c.127-165C>T		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.94-165C>T		intron	N/A	ENSP00000366093.2	Q92753-1
	RORB	ENST00000396204.2	TSL:1	c.127-165C>T		intron	N/A	ENSP00000379507.2	Q92753-2
	ENSG00000286944	ENST00000658390.1		n.2867-1344G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.296 AC: 44937 AN: 151990 Hom.: 7113 Cov.: 33

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.295

Gnomad AMR AF: 0.362

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.556

Gnomad SAS AF: 0.371

Gnomad FIN AF: 0.317

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.319

Gnomad OTH AF: 0.296

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

GnomAD4 genome AF: 0.296 AC: 44969 AN: 152108 Hom.: 7125 Cov.: 33 AF XY: 0.302 AC XY: 22483 AN XY: 74338

African (AFR) AF: 0.186 AC: 7711 AN: 41522

American (AMR) AF: 0.362 AC: 5541 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 1054 AN: 3472

East Asian (EAS) AF: 0.557 AC: 2874 AN: 5164

South Asian (SAS) AF: 0.372 AC: 1794 AN: 4828

European-Finnish (FIN) AF: 0.317 AC: 3347 AN: 10564

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.319 AC: 21687 AN: 67958

Other (OTH) AF: 0.292 AC: 616 AN: 2108

Alfa AF: 0.311 Hom.: 4699

Bravo AF: 0.292

Asia WGS AF: 0.388 AC: 1346 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.0
DANN	Benign	0.32
PhyloP100		0.57
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: rs3750420; hg19: chr9-77249382;