NM_006914.4:c.1225-639G>A

Variant names:

• chr9-74684824-G-A
• rs11144062
• NM_006914.4:c.1225-639G>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.1225-639G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 152,088 control chromosomes in the GnomAD database, including 2,503 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 0.17 (2503 hom., cov: 31)
• Consequence: RORB NM_006914.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.706
• 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):

• 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=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.189 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RORB	NM_006914.4	MANE Select	c.1225-639G>A		intron	N/A	NP_008845.2
	RORB	NM_001365023.1		c.1258-639G>A		intron	N/A	NP_001351952.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RORB	ENST00000376896.8	TSL:1 MANE Select	c.1225-639G>A		intron	N/A	ENSP00000366093.2
	RORB	ENST00000396204.2	TSL:1	c.1258-639G>A		intron	N/A	ENSP00000379507.2

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26076 AN: 151968 Hom.: 2502 Cov.: 31

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.261

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.193

Gnomad EAS AF: 0.00559

Gnomad SAS AF: 0.0791

Gnomad FIN AF: 0.237

Gnomad MID AF: 0.191

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.173

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

GnomAD4 genome AF: 0.171 AC: 26078 AN: 152088 Hom.: 2503 Cov.: 31 AF XY: 0.170 AC XY: 12653 AN XY: 74342

African (AFR) AF: 0.161 AC: 6695 AN: 41494

American (AMR) AF: 0.137 AC: 2091 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 669 AN: 3468

East Asian (EAS) AF: 0.00560 AC: 29 AN: 5176

South Asian (SAS) AF: 0.0775 AC: 374 AN: 4828

European-Finnish (FIN) AF: 0.237 AC: 2502 AN: 10556

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.192 AC: 13063 AN: 67972

Other (OTH) AF: 0.171 AC: 361 AN: 2112

Alfa AF: 0.181 Hom.: 11527

Bravo AF: 0.166

Asia WGS AF: 0.0500 AC: 175 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.2
DANN	Benign	0.70
PhyloP100		0.71
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: rs11144062; hg19: chr9-77299740;