1-161236108-G-T

Position:

• chr1-161236108-G-T

Variant summary

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

The NM_005122.5(NR1I3):​c.108-131C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,045,210 control chromosomes in the GnomAD database, including 12,997 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 0.12 (1348 hom., cov: 31)
  • Exomes 𝑓: 0.16 (11649 hom.)
• Consequence: NR1I3 NM_005122.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.418

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=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.213 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR1I3	NM_005122.5	c.108-131C>A		intron_variant		ENST00000367983.9	NP_005113.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR1I3	ENST00000367983.9	c.108-131C>A		intron_variant		1	NM_005122.5	ENSP00000356962	P4

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18589 AN: 152108 Hom.: 1344 Cov.: 31

Gnomad AFR AF: 0.0406

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.223

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.132

GnomAD4 exome AF: 0.157 AC: 140248 AN: 892984 Hom.: 11649 Cov.: 12 AF XY: 0.156 AC XY: 70072 AN XY: 448332

Gnomad4 AFR exome AF: 0.0382

Gnomad4 AMR exome AF: 0.131

Gnomad4 ASJ exome AF: 0.0990

Gnomad4 EAS exome AF: 0.260

Gnomad4 SAS exome AF: 0.159

Gnomad4 FIN exome AF: 0.145

Gnomad4 NFE exome AF: 0.159

Gnomad4 OTH exome AF: 0.147

GnomAD4 genome AF: 0.122 AC: 18605 AN: 152226 Hom.: 1348 Cov.: 31 AF XY: 0.124 AC XY: 9211 AN XY: 74426

Gnomad4 AFR AF: 0.0405

Gnomad4 AMR AF: 0.129

Gnomad4 ASJ AF: 0.101

Gnomad4 EAS AF: 0.223

Gnomad4 SAS AF: 0.165

Gnomad4 FIN AF: 0.146

Gnomad4 NFE AF: 0.157

Gnomad4 OTH AF: 0.131

Alfa AF: 0.125 Hom.: 580

Bravo AF: 0.118

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.2
DANN	Benign	0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs6686001; hg19: chr1-161205898; COSMIC: COSV63469149; COSMIC: COSV63469149;