NM_005122.5:c.239-1089T>C

Variant names:

• chr1-161234427-A-G
• rs3003596
• NM_005122.5:c.239-1089T>C

Variant summary

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

The NM_005122.5(NR1I3):​c.239-1089T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.453 in 151,446 control chromosomes in the GnomAD database, including 15,741 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 0.45 (15741 hom., cov: 31)
• Consequence: NR1I3 NM_005122.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.504
• Publications: 30 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.537 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1I3	NM_005122.5	c.239-1089T>C		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.239-1089T>C		intron_variant	Intron 3 of 8	1	NM_005122.5	ENSP00000356962.5

Frequencies

GnomAD3 genomes AF: 0.453 AC: 68544 AN: 151330 Hom.: 15712 Cov.: 31

Gnomad AFR AF: 0.488

Gnomad AMI AF: 0.451

Gnomad AMR AF: 0.461

Gnomad ASJ AF: 0.374

Gnomad EAS AF: 0.553

Gnomad SAS AF: 0.472

Gnomad FIN AF: 0.464

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.423

Gnomad OTH AF: 0.445

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

GnomAD4 genome AF: 0.453 AC: 68627 AN: 151446 Hom.: 15741 Cov.: 31 AF XY: 0.456 AC XY: 33773 AN XY: 74032

African (AFR) AF: 0.488 AC: 20211 AN: 41418

American (AMR) AF: 0.462 AC: 7058 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.374 AC: 1275 AN: 3410

East Asian (EAS) AF: 0.554 AC: 2860 AN: 5166

South Asian (SAS) AF: 0.472 AC: 2267 AN: 4804

European-Finnish (FIN) AF: 0.464 AC: 4894 AN: 10538

Middle Eastern (MID) AF: 0.425 AC: 125 AN: 294

European-Non Finnish (NFE) AF: 0.423 AC: 28600 AN: 67580

Other (OTH) AF: 0.451 AC: 947 AN: 2100

Alfa AF: 0.434 Hom.: 19634

Bravo AF: 0.459

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.3
DANN	Benign	0.45
PhyloP100		0.50
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: rs3003596; hg19: chr1-161204217; COSMIC: COSV107457374; COSMIC: COSV107457374;