1-161233437-G-A

Position:

• chr1-161233437-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000367983.9(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 ENST00000367983.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.635

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
NR1I3	NM_005122.5	c.239-99C>T		intron_variant		ENST00000367983.9	NP_005113.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR1I3	ENST00000367983.9	c.239-99C>T		intron_variant		1	NM_005122.5	ENSP00000356962	P4

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

Gnomad4 AFR exome AF: 0.331

Gnomad4 AMR exome AF: 0.380

Gnomad4 ASJ exome AF: 0.254

Gnomad4 EAS exome AF: 0.434

Gnomad4 SAS exome AF: 0.274

Gnomad4 FIN exome AF: 0.288

Gnomad4 NFE exome AF: 0.248

Gnomad4 OTH exome AF: 0.281

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

Gnomad4 AFR AF: 0.312

Gnomad4 AMR AF: 0.323

Gnomad4 ASJ AF: 0.260

Gnomad4 EAS AF: 0.427

Gnomad4 SAS AF: 0.283

Gnomad4 FIN AF: 0.291

Gnomad4 NFE AF: 0.244

Gnomad4 OTH AF: 0.296

Alfa AF: 0.259 Hom.: 1392

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs2502815; hg19: chr1-161203227; COSMIC: COSV63469785; COSMIC: COSV63469785;