rs34161743

Variant names:

• chr1-161233288-G-A
• rs34161743
• NM_005122.5:c.289C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-161233288-G-A
• chr1-161233288-G-C
• chr1-161233288-G-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

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
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.01
• Publications: 6 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]

TOMM40L (HGNC:25756): (translocase of outer mitochondrial membrane 40 like) Predicted to enable protein transmembrane transporter activity. Predicted to be involved in protein import into mitochondrial matrix. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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 VariationId is 283162.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 268 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005122.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR1I3	NM_005122.5	MANE Select	c.289C>T	p.Arg97Trp	missense	Exon 4 of 9	NP_005113.1	Q14994-2
	NR1I3	NM_001077482.3		c.289C>T	p.Arg97Trp	missense	Exon 4 of 9	NP_001070950.1	Q14994-8
	NR1I3	NM_001077480.3		c.289C>T	p.Arg97Trp	missense	Exon 4 of 9	NP_001070948.1	Q14994-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR1I3	ENST00000367983.9	TSL:1 MANE Select	c.289C>T	p.Arg97Trp	missense	Exon 4 of 9	ENSP00000356962.5	Q14994-2
	NR1I3	ENST00000367979.6	TSL:1	c.289C>T	p.Arg97Trp	missense	Exon 3 of 8	ENSP00000356958.2	Q14994-8
	NR1I3	ENST00000367982.8	TSL:1	c.289C>T	p.Arg97Trp	missense	Exon 4 of 9	ENSP00000356961.4	Q14994-1

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 268 AN: 152178 Hom.: 1 Cov.: 32

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

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

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

GnomAD4 genome AF: 0.00176 AC: 268 AN: 152296 Hom.: 1 Cov.: 32 AF XY: 0.00167 AC XY: 124 AN XY: 74460

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

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)
-	-	1	NR1I3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.013	T
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		1.0
PrimateAI	Benign	0.35	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.50
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	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

Other links and lift over

dbSNP: rs34161743; hg19: chr1-161203078;