rs2502815

Variant names:

• chr1-161233437-G-A
• rs2502815
• NM_005122.5:c.239-99C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-161233437-G-A
• chr1-161233437-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005122.5(NR1I3):​c.239-99C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.267 in 1,273,808 control chromosomes in the GnomAD database, including 47,121 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 0.28 (6300 hom., cov: 32)
  • Exomes 𝑓: 0.26 (40821 hom.)
• Consequence: NR1I3 NM_005122.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.635
• Publications: 25 publications found

Genes affected

NR1I3 (HGNC:7969): (nuclear receptor subfamily 1 group I member 3) This gene encodes a member of the nuclear receptor superfamily, and is a key regulator of xenobiotic and endobiotic metabolism. The protein binds to DNA as a monomer or a heterodimer with the retinoid X receptor and regulates the transcription of target genes involved in drug metabolism and bilirubin clearance, such as cytochrome P450 family members. Unlike most nuclear receptors, this transcriptional regulator is constitutively active in the absence of ligand but is regulated by both agonists and inverse agonists. Ligand binding results in translocation of this protein to the nucleus, where it activates or represses target gene transcription. These ligands include bilirubin, a variety of foreign compounds, steroid hormones, and prescription drugs. In addition to drug metabolism, the CAR protein is also reported to regulate genes involved in glucose metabolism, lipid metabolism, cell proliferation, and circadian clock regulation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2020]

NR1I3 Gene-Disease associations (from GenCC):

• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.412 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1I3	NM_005122.5	c.239-99C>T		intron_variant	Intron 3 of 8	ENST00000367983.9	NP_005113.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR1I3	ENST00000367983.9	c.239-99C>T		intron_variant	Intron 3 of 8	1	NM_005122.5	ENSP00000356962.5

Frequencies

GnomAD3 genomes AF: 0.283 AC: 42926 AN: 151912 Hom.: 6292 Cov.: 32

Gnomad AFR AF: 0.312

Gnomad AMI AF: 0.253

Gnomad AMR AF: 0.323

Gnomad ASJ AF: 0.260

Gnomad EAS AF: 0.427

Gnomad SAS AF: 0.282

Gnomad FIN AF: 0.291

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.244

Gnomad OTH AF: 0.289

GnomAD4 exome AF: 0.265 AC: 297223 AN: 1121778 Hom.: 40821 AF XY: 0.264 AC XY: 148037 AN XY: 561730

African (AFR) AF: 0.331 AC: 8836 AN: 26732

American (AMR) AF: 0.380 AC: 14067 AN: 36996

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 5302 AN: 20912

East Asian (EAS) AF: 0.434 AC: 16250 AN: 37422

South Asian (SAS) AF: 0.274 AC: 19672 AN: 71706

European-Finnish (FIN) AF: 0.288 AC: 10750 AN: 37388

Middle Eastern (MID) AF: 0.274 AC: 920 AN: 3360

European-Non Finnish (NFE) AF: 0.248 AC: 207740 AN: 838636

Other (OTH) AF: 0.281 AC: 13686 AN: 48626

GnomAD4 genome AF: 0.283 AC: 42969 AN: 152030 Hom.: 6300 Cov.: 32 AF XY: 0.286 AC XY: 21220 AN XY: 74304

African (AFR) AF: 0.312 AC: 12935 AN: 41466

American (AMR) AF: 0.323 AC: 4937 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.260 AC: 904 AN: 3472

East Asian (EAS) AF: 0.427 AC: 2205 AN: 5164

South Asian (SAS) AF: 0.283 AC: 1361 AN: 4816

European-Finnish (FIN) AF: 0.291 AC: 3073 AN: 10556

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.244 AC: 16607 AN: 67958

Other (OTH) AF: 0.296 AC: 626 AN: 2116

Alfa AF: 0.267 Hom.: 1652

Bravo AF: 0.296

Asia WGS AF: 0.352 AC: 1221 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	12
DANN	Benign	0.41
PhyloP100		0.64
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs2502815; hg19: chr1-161203227; COSMIC: COSV63469785; COSMIC: COSV63469785;