rs869312972

Positions:

• chr9-74685486-CACG-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM4_Supporting PP5_Moderate

The NM_006914.4(RORB):​c.1249_1251delACG​(p.Thr417del) variant causes a conservative inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RORB NM_006914.4 conservative_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 4.35

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_006914.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 9-74685486-CACG-C is Pathogenic according to our data. Variant chr9-74685486-CACG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 225116.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RORB	NM_006914.4	c.1249_1251delACG	p.Thr417del	conservative_inframe_deletion	10/10	ENST00000376896.8	NP_008845.2
RORB	NM_001365023.1	c.1282_1284delACG	p.Thr428del	conservative_inframe_deletion	10/10		NP_001351952.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RORB	ENST00000376896.8	c.1249_1251delACG	p.Thr417del	conservative_inframe_deletion	10/10	1	NM_006914.4	ENSP00000366093.2
RORB	ENST00000396204.2	c.1282_1284delACG	p.Thr428del	conservative_inframe_deletion	10/10	1		ENSP00000379507.2

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

-

LIKELY POSITIVE: Relevant Alteration(s) Detected -

Epilepsy, idiopathic generalized, susceptibility to, 15 Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Mar 14, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs869312972; hg19: chr9-77300402;