rs1555423812

chr15-60511240-GAC-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_134261.3(RORA):c.804_805del(p.Ser269HisfsTer13) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RORA NM_134261.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 7.23

Genes affected

RORA (HGNC:10258): (RAR related orphan receptor A) The protein encoded by this gene is a member of the NR1 subfamily of nuclear hormone receptors. It 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, as well as with NM23-1, the product of a tumor metastasis suppressor candidate gene. Also, it has been shown to aid in the transcriptional regulation of some genes involved in circadian rhythm. Four transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Feb 2014]

RORA-AS1 (HGNC:51410): (RORA antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 15-60511240-GAC-G is Pathogenic according to our data. Variant chr15-60511240-GAC-G is described in ClinVar as [Pathogenic]. Clinvar id is 549841.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-60511240-GAC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RORA	NM_134261.3	c.804_805del	p.Ser269HisfsTer13	frameshift_variant	5/11	ENST00000335670.11
RORA-AS1	NR_120342.1	n.415+711_415+712del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RORA	ENST00000335670.11	c.804_805del	p.Ser269HisfsTer13	frameshift_variant	5/11	1	NM_134261.3
RORA-AS1	ENST00000559824.5	n.415+711_415+712del		intron_variant, non_coding_transcript_variant		3

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: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Uncertain significance and reported on 04-24-2017 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 21, 2018	The c.903_904delGT variant in the RORA gene identified in this individual has now been published as a pathogenic variant associated with a RORA-related disorder (Guissart et al., 2018). To our knowledge, this individual represents the only reported individual to harbor this variant. The c.903_904delGT variant causes a frameshift starting with codon Serine 302, changes this amino acid to a Histidine residue, and creates a premature Stop codon at position 13 of the new reading frame, denoted p.Ser302HisfsX13. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.903_904delGT variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.903_904delGT as a pathogenic variant. -

Intellectual developmental disorder with or without epilepsy or cerebellar ataxia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 27, 2018

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555423812; hg19: chr15-60803439;