chr15-60948405-T-C

Variant names:

• chr15-60948405-T-C
• rs4335725
• NM_134261.3:c.167-269719A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_134261.3(RORA):​c.167-269719A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.691 in 152,158 control chromosomes in the GnomAD database, including 36,592 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.69 (36592 hom., cov: 33)
• Consequence: RORA NM_134261.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.793
• Publications: 8 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 Gene-Disease associations (from GenCC):

• intellectual developmental disorder with or without epilepsy or cerebellar ataxia

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.841 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RORA	NM_134261.3	c.167-269719A>G		intron_variant	Intron 1 of 10	ENST00000335670.11	NP_599023.1
RORA	XM_047432928.1	c.-1751-269719A>G		intron_variant	Intron 1 of 10		XP_047288884.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RORA	ENST00000335670.11	c.167-269719A>G		intron_variant	Intron 1 of 10	1	NM_134261.3	ENSP00000335087.6

Frequencies

GnomAD3 genomes AF: 0.691 AC: 105025 AN: 152040 Hom.: 36553 Cov.: 33

Gnomad AFR AF: 0.640

Gnomad AMI AF: 0.700

Gnomad AMR AF: 0.765

Gnomad ASJ AF: 0.718

Gnomad EAS AF: 0.835

Gnomad SAS AF: 0.863

Gnomad FIN AF: 0.726

Gnomad MID AF: 0.642

Gnomad NFE AF: 0.675

Gnomad OTH AF: 0.683

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

GnomAD4 genome AF: 0.691 AC: 105122 AN: 152158 Hom.: 36592 Cov.: 33 AF XY: 0.699 AC XY: 51985 AN XY: 74368

African (AFR) AF: 0.640 AC: 26551 AN: 41482

American (AMR) AF: 0.765 AC: 11703 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.718 AC: 2492 AN: 3472

East Asian (EAS) AF: 0.835 AC: 4330 AN: 5184

South Asian (SAS) AF: 0.863 AC: 4167 AN: 4830

European-Finnish (FIN) AF: 0.726 AC: 7675 AN: 10574

Middle Eastern (MID) AF: 0.653 AC: 192 AN: 294

European-Non Finnish (NFE) AF: 0.675 AC: 45924 AN: 68010

Other (OTH) AF: 0.687 AC: 1450 AN: 2110

Alfa AF: 0.684 Hom.: 52763

Bravo AF: 0.689

Asia WGS AF: 0.816 AC: 2836 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	5.0
DANN	Benign	0.82
PhyloP100		-0.79
Mutation Taster		=100/0	polymorphism (auto)

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

dbSNP: rs4335725; hg19: chr15-61240604;