rs2501873

Variant names:

• chr1-161234748-C-T
• rs2501873
• NM_005122.5:c.238+1099G>A

Variant summary

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

The NM_005122.5(NR1I3):​c.238+1099G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.504 in 152,012 control chromosomes in the GnomAD database, including 20,167 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 0.50 (20167 hom., cov: 32)
• Consequence: NR1I3 NM_005122.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.276
• Publications: 16 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.65 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1I3	NM_005122.5	c.238+1099G>A		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.238+1099G>A		intron_variant	Intron 3 of 8	1	NM_005122.5	ENSP00000356962.5

Frequencies

GnomAD3 genomes AF: 0.504 AC: 76493 AN: 151894 Hom.: 20120 Cov.: 32

Gnomad AFR AF: 0.657

Gnomad AMI AF: 0.473

Gnomad AMR AF: 0.483

Gnomad ASJ AF: 0.376

Gnomad EAS AF: 0.555

Gnomad SAS AF: 0.475

Gnomad FIN AF: 0.467

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.427

Gnomad OTH AF: 0.479

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

GnomAD4 genome AF: 0.504 AC: 76601 AN: 152012 Hom.: 20167 Cov.: 32 AF XY: 0.505 AC XY: 37541 AN XY: 74278

African (AFR) AF: 0.657 AC: 27240 AN: 41462

American (AMR) AF: 0.483 AC: 7391 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.376 AC: 1306 AN: 3470

East Asian (EAS) AF: 0.555 AC: 2867 AN: 5166

South Asian (SAS) AF: 0.475 AC: 2290 AN: 4824

European-Finnish (FIN) AF: 0.467 AC: 4923 AN: 10540

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.427 AC: 29012 AN: 67948

Other (OTH) AF: 0.484 AC: 1021 AN: 2108

Alfa AF: 0.449 Hom.: 66146

Bravo AF: 0.517

Asia WGS AF: 0.533 AC: 1848 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	6.3
DANN	Benign	0.80
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2501873; hg19: chr1-161204538;