1-161231463-A-G

Position:

chr1-161231463-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005122.5(NR1I3):c.560T>C(p.Ile187Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000197 in 1,577,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

NR1I3
NM_005122.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.95

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:

NR1I3 (HGNC:):

NR1I3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13052532).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR1I3	NM_005122.5 linkuse as main transcript	c.560T>C	p.Ile187Thr	missense_variant	6/9	ENST00000367983.9	NP_005113.1	Q14994-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR1I3	ENST00000367983.9 linkuse as main transcript	c.560T>C	p.Ile187Thr	missense_variant	6/9	1	NM_005122.5	ENSP00000356962.5		Q14994-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000833

AC:

AN:

216194

Hom.:

AF XY:

0.0000680

AC XY:

AN XY:

117576

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00107

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000958

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000211

AC:

AN:

1424928

Hom.:

Cov.:

AF XY:

0.0000198

AC XY:

AN XY:

708476

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000707

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000376

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.0000988

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 05, 2024

The c.560T>C (p.I187T) alteration is located in exon 6 (coding exon 5) of the NR1I3 gene. This alteration results from a T to C substitution at nucleotide position 560, causing the isoleucine (I) at amino acid position 187 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.59

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

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;T;D;T;T;T;D;T;D;D;D;D;D;D;D;.;T;D

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.13

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

MetaSVM

Uncertain

0.55

MutationAssessor

Benign

1.3

.;L;.;L;L;.;L;L;.;L;.;.;.;.;L;L;L;.;.

MutationTaster

Benign

1.0

D;D;D;D;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-2.2

N;N;N;N;N;N;N;N;N;N;N;N;N;D;N;N;N;N;N

REVEL

Uncertain

0.46

Sift

Benign

0.063

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

Sift4G

Uncertain

0.0030

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

Polyphen

0.0040, 0.29, 0.0080, 0.0010

.;.;.;.;.;.;.;.;.;B;.;.;.;B;.;.;.;B;B

Vest4

0.35

MutPred

0.61

.;Gain of glycosylation at I187 (P = 0.0356);.;Gain of glycosylation at I187 (P = 0.0356);Gain of glycosylation at I187 (P = 0.0356);.;Gain of glycosylation at I187 (P = 0.0356);Gain of glycosylation at I187 (P = 0.0356);.;Gain of glycosylation at I187 (P = 0.0356);.;.;.;.;Gain of glycosylation at I187 (P = 0.0356);Gain of glycosylation at I187 (P = 0.0356);Gain of glycosylation at I187 (P = 0.0356);.;Gain of glycosylation at I187 (P = 0.0356);

MVP

0.97

MPC

0.25

ClinPred

0.16

GERP RS

5.9

Varity_R

0.34

gMVP

0.34

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over