Genetic Variant NM_134261.3:c.1383C>A (chr15-60499916-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_134261.3(RORA):c.1383C>A(p.His461Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,224 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H461R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RORA
NM_134261.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.47

Publications

0 publications found

Variant links:

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 links:

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

RORA-AS1 links:

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ACMG classification

Classification was made for transcript

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RORA	NM_134261.3	MANE Select	c.1383C>A	p.His461Gln	missense	Exon 10 of 11	NP_599023.1	P35398-2
RORA	NM_134260.3		c.1482C>A	p.His494Gln	missense	Exon 11 of 12	NP_599022.1	P35398-1
RORA	NM_002943.4		c.1458C>A	p.His486Gln	missense	Exon 10 of 11	NP_002934.1	A0A0C4DFP5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RORA	ENST00000335670.11	TSL:1 MANE Select	c.1383C>A	p.His461Gln	missense	Exon 10 of 11	ENSP00000335087.6	P35398-2
RORA	ENST00000261523.9	TSL:1	c.1482C>A	p.His494Gln	missense	Exon 11 of 12	ENSP00000261523.5	P35398-1
RORA	ENST00000309157.8	TSL:1	c.1458C>A	p.His486Gln	missense	Exon 10 of 11	ENSP00000309753.3	A0A0C4DFP5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1457224

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725270

show subpopulations

African (AFR)

AF:

0.0000301

AC:

AN:

33204

American (AMR)

AF:

0.00

AC:

AN:

44244

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26038

East Asian (EAS)

AF:

0.00

AC:

AN:

39592

South Asian (SAS)

AF:

0.00

AC:

AN:

85978

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53138

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1109054

Other (OTH)

AF:

0.00

AC:

AN:

60226

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.71

Eigen

Benign

-0.015

Eigen_PC

Benign

0.075

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.85

M_CAP

Uncertain

0.098

MetaRNN

Uncertain

0.47

MetaSVM

Uncertain

0.60

MutationAssessor

Benign

1.7

PhyloP100

2.5

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-4.5

REVEL

Pathogenic

0.67

Sift

Benign

0.062

Sift4G

Uncertain

0.025

Vest4

0.53

MVP

0.90

MPC

1.1

ClinPred

0.94

GERP RS

2.7

Varity_R

0.79

gMVP

0.72

Mutation Taster

=4/96

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over