15-60501002-T-G

Variant names:

• chr15-60501002-T-G
• NM_134261.3:c.1251A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_134261.3(RORA):​c.1251A>C​(p.Glu417Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,768 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RORA NM_134261.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.34
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_134261.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RORA	NM_134261.3	MANE Select	c.1251A>C	p.Glu417Asp	missense	Exon 9 of 11	NP_599023.1	P35398-2
	RORA	NM_134260.3		c.1350A>C	p.Glu450Asp	missense	Exon 10 of 12	NP_599022.1	P35398-1
	RORA	NM_002943.4		c.1326A>C	p.Glu442Asp	missense	Exon 9 of 11	NP_002934.1	A0A0C4DFP5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RORA	ENST00000335670.11	TSL:1 MANE Select	c.1251A>C	p.Glu417Asp	missense	Exon 9 of 11	ENSP00000335087.6	P35398-2
	RORA	ENST00000261523.9	TSL:1	c.1350A>C	p.Glu450Asp	missense	Exon 10 of 12	ENSP00000261523.5	P35398-1
	RORA	ENST00000309157.8	TSL:1	c.1326A>C	p.Glu442Asp	missense	Exon 9 of 11	ENSP00000309753.3	A0A0C4DFP5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457768 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 725506

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33372

American (AMR) AF: 0.00 AC: 0 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39574

South Asian (SAS) AF: 0.00 AC: 0 AN: 86068

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108646

Other (OTH) AF: 0.00 AC: 0 AN: 60244

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Intellectual developmental disorder with or without epilepsy or cerebellar ataxia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.18
Eigen_PC	Benign	0.041
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.095	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Uncertain	0.021	D
MutationAssessor	Benign	1.1	L
PhyloP100		1.3
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.46
Sift	Benign	0.093	T
Sift4G	Benign	0.16	T
Vest4		0.60
MVP		0.98
MPC		0.90
ClinPred		0.60	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.51
Mutation Taster		=13/87	disease causing

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

hg19: chr15-60793201;