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GeneBe

15-60499995-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate

The NM_134261.3(RORA):c.1304G>A(p.Trp435Ter) variant causes a stop gained 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 Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

RORA
NM_134261.3 stop_gained

Scores

5
1
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.84
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-AS1 (HGNC:51410): (RORA antisense RNA 1)

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 15-60499995-C-T is Pathogenic according to our data. Variant chr15-60499995-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2501285.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RORANM_134261.3 linkuse as main transcriptc.1304G>A p.Trp435Ter stop_gained 10/11 ENST00000335670.11
RORA-AS1NR_120342.1 linkuse as main transcriptn.290-10413C>T intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RORAENST00000335670.11 linkuse as main transcriptc.1304G>A p.Trp435Ter stop_gained 10/111 NM_134261.3 P35398-2
RORA-AS1ENST00000559824.5 linkuse as main transcriptn.290-10413C>T intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
27
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Intellectual developmental disorder with or without epilepsy or cerebellar ataxia Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMar 28, 2023Variant summary: RORA c.1304G>A (p.Trp435X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation and a missense change downstream of this position have been reported in affected individuals (HGMD), suggesting a functional importance for the deleted protein region. The variant was absent in 249540 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1304G>A in individuals affected with Intellectual Developmental Disorder with or without Epilepsy or Cerebellar Ataxia and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.66
CADD
Pathogenic
44
DANN
Uncertain
0.99
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.99
D
MutationTaster
Benign
1.0
A;A;A;A
Vest4
0.93
GERP RS
5.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-60792194; API