Genetic Variant NM_005122.5:c.289C>G (chr1-161233288-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_005122.5(NR1I3):c.289C>G(p.Arg97Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R97W) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

NR1I3
NM_005122.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.01

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.42240196).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1I3	NM_005122.5 link	c.289C>G	p.Arg97Gly	missense_variant	Exon 4 of 9	ENST00000367983.9	NP_005113.1	Q14994-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR1I3	ENST00000367983.9 link	c.289C>G	p.Arg97Gly	missense_variant	Exon 4 of 9	1	NM_005122.5	ENSP00000356962.5		Q14994-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;.;.

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.91

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.42

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.73

MutationAssessor

Uncertain

2.7

.;M;.;M;M;.;M;M;.;M;.;.;.;.;M;M;M;.;.

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-3.7

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

REVEL

Uncertain

0.51

Sift

Uncertain

0.022

D;D;D;D;D;T;D;D;D;D;D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.020

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

0.89, 0.99, 0.059

.;.;.;.;.;.;.;.;.;P;.;.;.;D;.;.;.;P;B

Vest4

0.32

MutPred

0.32

.;Loss of MoRF binding (P = 0.0497);.;Loss of MoRF binding (P = 0.0497);Loss of MoRF binding (P = 0.0497);.;Loss of MoRF binding (P = 0.0497);Loss of MoRF binding (P = 0.0497);.;Loss of MoRF binding (P = 0.0497);.;.;.;.;Loss of MoRF binding (P = 0.0497);Loss of MoRF binding (P = 0.0497);Loss of MoRF binding (P = 0.0497);.;Loss of MoRF binding (P = 0.0497);

MVP

0.99

MPC

0.54

ClinPred

0.96

GERP RS

2.9

Varity_R

0.32

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over