Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_134261.3(RORA):c.1268_1291delinsAT(p.Phe423TyrfsTer11) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.


Genomes: not found (cov: 32)


NM_134261.3 frameshift


Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1


PhyloP100: 9.41
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 Pathogenic. Variant got 12 ACMG points.

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
Very rare variant in population databases, with high coverage;
Variant 15-60500962-CTGACATCAGTACAAATGCAGAAA-AT is Pathogenic according to our data. Variant chr15-60500962-CTGACATCAGTACAAATGCAGAAA-AT is described in ClinVar as [Pathogenic]. Clinvar id is 2304091.Status of the report is criteria_provided_single_submitter, 1 stars.



Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RORANM_134261.3 linkuse as main transcriptc.1268_1291delinsAT p.Phe423TyrfsTer11 frameshift_variant 9/11 ENST00000335670.11
RORA-AS1NR_120342.1 linkuse as main transcriptn.290-9446_290-9423delinsAT intron_variant, non_coding_transcript_variant


Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RORAENST00000335670.11 linkuse as main transcriptc.1268_1291delinsAT p.Phe423TyrfsTer11 frameshift_variant 9/111 NM_134261.3 P35398-2
RORA-AS1ENST00000559824.5 linkuse as main transcriptn.290-9446_290-9423delinsAT intron_variant, non_coding_transcript_variant 3


GnomAD3 genomes
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome


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

Submissions by phenotype

Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsAug 12, 2022The c.1268_1291del24insAT (p.F423Yfs*11) alteration, located in exon 9 (coding exon 9) of the RORA gene, consists of a deletion of 24 and insertion of 2 nucleotides causing a translational frameshift at position 1268 with a predicted alternate stop codon after 11 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Calibrated prediction


Find out detailed SpliceAI scores and Pangolin per-transcript scores at


No publications associated with this variant yet.

Other links and lift over

hg19: chr15-60793161; API