rs2307424

chr1-161232815-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005122.5(NR1I3):c.540C>T(p.Pro180=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.342 in 1,613,446 control chromosomes in the GnomAD database, including 97,523 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7320 hom., cov: 32)
  • Exomes 𝑓: 0.35 (90203 hom.)
• Consequence: NR1I3 NM_005122.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.19

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 1-161232815-G-A is Benign according to our data. Variant chr1-161232815-G-A is described in ClinVar as [Benign]. Clinvar id is 197772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.19 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.504 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR1I3	NM_005122.5	c.540C>T	p.Pro180=	synonymous_variant	5/9	ENST00000367983.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR1I3	ENST00000367983.9	c.540C>T	p.Pro180=	synonymous_variant	5/9	1	NM_005122.5	P4

Frequencies

GnomAD3 genomes AF: 0.294 AC: 44736 AN: 152006 Hom.: 7317 Cov.: 32

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.322

Gnomad AMR AF: 0.346

Gnomad ASJ AF: 0.319

Gnomad EAS AF: 0.521

Gnomad SAS AF: 0.397

Gnomad FIN AF: 0.317

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.344

Gnomad OTH AF: 0.308

GnomAD3 exomes AF: 0.355 AC: 89158 AN: 251418 Hom.: 16749 AF XY: 0.357 AC XY: 48535 AN XY: 135896

Gnomad AFR exome AF: 0.138

Gnomad AMR exome AF: 0.386

Gnomad ASJ exome AF: 0.327

Gnomad EAS exome AF: 0.526

Gnomad SAS exome AF: 0.395

Gnomad FIN exome AF: 0.315

Gnomad NFE exome AF: 0.347

Gnomad OTH exome AF: 0.354

GnomAD4 exome AF: 0.347 AC: 507145 AN: 1461322 Hom.: 90203 Cov.: 37 AF XY: 0.348 AC XY: 252857 AN XY: 726998

Gnomad4 AFR exome AF: 0.136

Gnomad4 AMR exome AF: 0.379

Gnomad4 ASJ exome AF: 0.329

Gnomad4 EAS exome AF: 0.524

Gnomad4 SAS exome AF: 0.388

Gnomad4 FIN exome AF: 0.315

Gnomad4 NFE exome AF: 0.345

Gnomad4 OTH exome AF: 0.342

GnomAD4 genome AF: 0.294 AC: 44749 AN: 152124 Hom.: 7320 Cov.: 32 AF XY: 0.296 AC XY: 22048 AN XY: 74390

Gnomad4 AFR AF: 0.145

Gnomad4 AMR AF: 0.347

Gnomad4 ASJ AF: 0.319

Gnomad4 EAS AF: 0.521

Gnomad4 SAS AF: 0.396

Gnomad4 FIN AF: 0.317

Gnomad4 NFE AF: 0.344

Gnomad4 OTH AF: 0.306

Alfa AF: 0.337 Hom.: 21073

Bravo AF: 0.288

Asia WGS AF: 0.453 AC: 1574 AN: 3478

EpiCase AF: 0.347

EpiControl AF: 0.346

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 02, 2014

- -

NR1I3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	9.0
Dann	Benign	0.84

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: rs2307424; hg19: chr1-161202605; COSMIC: COSV63468926; COSMIC: COSV63468926;