rs1555427498

Positions:

• chr15-60531773-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_134261.3(RORA):​c.275G>C​(p.Gly92Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RORA NM_134261.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.91

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935
• PP5: Variant 15-60531773-C-G is Pathogenic according to our data. Variant chr15-60531773-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 549843.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-60531773-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RORA	NM_134261.3	c.275G>C	p.Gly92Ala	missense_variant	3/11	ENST00000335670.11	NP_599023.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RORA	ENST00000335670.11	c.275G>C	p.Gly92Ala	missense_variant	3/11	1	NM_134261.3	ENSP00000335087.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual developmental disorder with or without epilepsy or cerebellar ataxia Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 27, 2018	- -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 27, 2020	The heterozygous p.Gly92Ala variant in RORA was identified by our study in an individual with intellectual developmental disorder with or without epilepsy or cerebellar ataxia (PMID: 29656859). Trio exome analysis showed this variant to be de novo. This variant was absent from large population studies and has been reported pathogenic by OMIM in ClinVar (Variation ID: 549843). In vitro functional studies provide some evidence that the p.Gly92Ala variant may impact protein function (PMID: 29656859). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Gly92Ala variant is located in a region of RORA that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 29656859). In summary, this variant meets criteria to be classified as pathogenic for intellectual developmental disorder with or without epilepsy or cerebellar ataxia in an autosomal dominant manner based on an affected individual with a de novo variant and in vitro functional studies. ACMG/AMP Criteria applied: PS2, PS3, PM2, PP3, PM1_Supporting (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;.;.;.;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.2	L;.;.;.;.
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-5.5	D;D;D;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;.
Vest4		0.85
MVP		0.98
MPC		2.2
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.90
gMVP		0.94

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: rs1555427498; hg19: chr15-60823972;