NM_006914.4:c.7+25042T>C

Variant names:

• chr9-74523025-T-C
• rs10491929
• NM_006914.4:c.7+25042T>C

Variant summary

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

The NM_006914.4(RORB):​c.7+25042T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.303 in 151,796 control chromosomes in the GnomAD database, including 8,830 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 (8830 hom., cov: 32)
• Consequence: RORB NM_006914.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.334
• Publications: 7 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=-0.72).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.416 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RORB	NM_006914.4	c.7+25042T>C		intron_variant	Intron 1 of 9	ENST00000376896.8	NP_008845.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RORB	ENST00000376896.8	c.7+25042T>C		intron_variant	Intron 1 of 9	1	NM_006914.4	ENSP00000366093.2

Frequencies

GnomAD3 genomes AF: 0.304 AC: 46058 AN: 151678 Hom.: 8832 Cov.: 32

Gnomad AFR AF: 0.0783

Gnomad AMI AF: 0.527

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.361

Gnomad EAS AF: 0.171

Gnomad SAS AF: 0.397

Gnomad FIN AF: 0.453

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.420

Gnomad OTH AF: 0.337

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

GnomAD4 genome AF: 0.303 AC: 46052 AN: 151796 Hom.: 8830 Cov.: 32 AF XY: 0.304 AC XY: 22583 AN XY: 74172

African (AFR) AF: 0.0781 AC: 3243 AN: 41526

American (AMR) AF: 0.278 AC: 4224 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.361 AC: 1249 AN: 3464

East Asian (EAS) AF: 0.171 AC: 874 AN: 5126

South Asian (SAS) AF: 0.397 AC: 1911 AN: 4808

European-Finnish (FIN) AF: 0.453 AC: 4786 AN: 10564

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.420 AC: 28465 AN: 67786

Other (OTH) AF: 0.339 AC: 714 AN: 2108

Alfa AF: 0.366 Hom.: 1475

Bravo AF: 0.274

Asia WGS AF: 0.348 AC: 1207 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	13
DANN	Benign	0.77
PhyloP100		0.33
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: rs10491929; hg19: chr9-77137941; COSMIC: COSV65334191;