chr1-161236108-G-T

Variant names:

• chr1-161236108-G-T
• rs6686001
• NM_005122.5:c.108-131C>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.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
• Publications: 7 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=-0.81).
• 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 rank	MANE	Protein	UniProt
NR1I3	NM_005122.5	c.108-131C>A		intron_variant	Intron 2 of 8	ENST00000367983.9	NP_005113.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR1I3	ENST00000367983.9	c.108-131C>A		intron_variant	Intron 2 of 8	1	NM_005122.5	ENSP00000356962.5

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

African (AFR) AF: 0.0382 AC: 789 AN: 20674

American (AMR) AF: 0.131 AC: 2588 AN: 19744

Ashkenazi Jewish (ASJ) AF: 0.0990 AC: 1623 AN: 16390

East Asian (EAS) AF: 0.260 AC: 8769 AN: 33724

South Asian (SAS) AF: 0.159 AC: 8802 AN: 55414

European-Finnish (FIN) AF: 0.145 AC: 6121 AN: 42086

Middle Eastern (MID) AF: 0.119 AC: 457 AN: 3856

European-Non Finnish (NFE) AF: 0.159 AC: 105108 AN: 660430

Other (OTH) AF: 0.147 AC: 5991 AN: 40666

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

African (AFR) AF: 0.0405 AC: 1684 AN: 41556

American (AMR) AF: 0.129 AC: 1964 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 351 AN: 3470

East Asian (EAS) AF: 0.223 AC: 1159 AN: 5188

South Asian (SAS) AF: 0.165 AC: 796 AN: 4822

European-Finnish (FIN) AF: 0.146 AC: 1547 AN: 10596

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.157 AC: 10642 AN: 67994

Other (OTH) AF: 0.131 AC: 277 AN: 2112

Alfa AF: 0.127 Hom.: 676

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
PhyloP100		-0.42
PromoterAI		-0.00050	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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