chr1-161233288-G-A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_005122.5(NR1I3):​c.289C>T​(p.Arg97Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000369 in 1,614,134 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R97Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0018 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

NR1I3
NM_005122.5 missense

Scores

5
8
6

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 1.01

Publications

6 publications found
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 Gene-Disease associations (from GenCC):
  • intellectual disability
    Inheritance: AD Classification: LIMITED Submitted by: G2P

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.01259926).
BP6
Variant 1-161233288-G-A is Benign according to our data. Variant chr1-161233288-G-A is described in ClinVar as [Benign]. Clinvar id is 283162.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High AC in GnomAd4 at 268 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NR1I3NM_005122.5 linkc.289C>T p.Arg97Trp 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
NR1I3ENST00000367983.9 linkc.289C>T p.Arg97Trp missense_variant Exon 4 of 9 1 NM_005122.5 ENSP00000356962.5 Q14994-2

Frequencies

GnomAD3 genomes
AF:
0.00176
AC:
268
AN:
152178
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00589
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000720
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.000471
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00144
GnomAD2 exomes
AF:
0.000465
AC:
117
AN:
251424
AF XY:
0.000316
show subpopulations
Gnomad AFR exome
AF:
0.00572
Gnomad AMR exome
AF:
0.000347
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad FIN exome
AF:
0.000185
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000224
AC:
327
AN:
1461838
Hom.:
0
Cov.:
32
AF XY:
0.000204
AC XY:
148
AN XY:
727218
show subpopulations
African (AFR)
AF:
0.00636
AC:
213
AN:
33480
American (AMR)
AF:
0.000335
AC:
15
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.0000464
AC:
4
AN:
86256
European-Finnish (FIN)
AF:
0.000243
AC:
13
AN:
53396
Middle Eastern (MID)
AF:
0.000521
AC:
3
AN:
5754
European-Non Finnish (NFE)
AF:
0.0000459
AC:
51
AN:
1112000
Other (OTH)
AF:
0.000464
AC:
28
AN:
60392
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.479
Heterozygous variant carriers
0
19
38
57
76
95
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
10
20
30
40
50
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00176
AC:
268
AN:
152296
Hom.:
1
Cov.:
32
AF XY:
0.00167
AC XY:
124
AN XY:
74460
show subpopulations
African (AFR)
AF:
0.00587
AC:
244
AN:
41572
American (AMR)
AF:
0.000719
AC:
11
AN:
15294
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5180
South Asian (SAS)
AF:
0.000208
AC:
1
AN:
4816
European-Finnish (FIN)
AF:
0.000471
AC:
5
AN:
10616
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.0000588
AC:
4
AN:
68030
Other (OTH)
AF:
0.00142
AC:
3
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.494
Heterozygous variant carriers
0
15
31
46
62
77
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000563
Hom.:
0
Bravo
AF:
0.00188
ESP6500AA
AF:
0.00567
AC:
25
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000544
AC:
66
EpiCase
AF:
0.000109
EpiControl
AF:
0.0000593

ClinVar

Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Sep 25, 2015
Eurofins Ntd Llc (ga)
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

NR1I3-related disorder Benign:1
Jun 14, 2022
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Uncertain
0.010
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.57
.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.
Eigen
Uncertain
0.48
Eigen_PC
Uncertain
0.41
FATHMM_MKL
Benign
0.68
D
LIST_S2
Uncertain
0.96
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D
M_CAP
Pathogenic
0.43
D
MetaRNN
Benign
0.013
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Pathogenic
0.85
D
MutationAssessor
Uncertain
2.7
.;M;.;M;M;.;M;M;.;M;.;.;.;.;M;M;M;.;.
PhyloP100
1.0
PrimateAI
Benign
0.35
T
PROVEAN
Pathogenic
-4.8
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL
Uncertain
0.50
Sift
Pathogenic
0.0
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
0.0020
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
1.0, 1.0, 1.0
.;.;.;.;.;.;.;.;.;D;.;.;.;D;.;.;.;D;D
Vest4
0.37
MVP
1.0
MPC
0.71
ClinPred
0.061
T
GERP RS
2.9
Varity_R
0.41
gMVP
0.69
Mutation Taster
=80/20
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs34161743; hg19: chr1-161203078; API