rs2307418

Positions:

• chr1-161230796-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005122.5(NR1I3):​c.917+17A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,613,778 control chromosomes in the GnomAD database, including 18,450 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1253 hom., cov: 31)
  • Exomes 𝑓: 0.15 (17197 hom.)
• Consequence: NR1I3 NM_005122.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.405

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-161230796-T-G is Benign according to our data. Variant chr1-161230796-T-G is described in ClinVar as [Benign]. Clinvar id is 95259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR1I3	NM_005122.5	c.917+17A>C		intron_variant		ENST00000367983.9	NP_005113.1
TOMM40L	NM_032174.6			downstream_gene_variant		ENST00000367988.8	NP_115550.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR1I3	ENST00000367983.9	c.917+17A>C		intron_variant		1	NM_005122.5	ENSP00000356962	P4
TOMM40L	ENST00000367988.8			downstream_gene_variant		2	NM_032174.6	ENSP00000356967	P1

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17490 AN: 152044 Hom.: 1254 Cov.: 31

Gnomad AFR AF: 0.0292

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.201

Gnomad EAS AF: 0.0878

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.124

GnomAD3 exomes AF: 0.131 AC: 32966 AN: 250878 Hom.: 2492 AF XY: 0.135 AC XY: 18291 AN XY: 135570

Gnomad AFR exome AF: 0.0258

Gnomad AMR exome AF: 0.0878

Gnomad ASJ exome AF: 0.213

Gnomad EAS exome AF: 0.0825

Gnomad SAS exome AF: 0.116

Gnomad FIN exome AF: 0.141

Gnomad NFE exome AF: 0.161

Gnomad OTH exome AF: 0.156

GnomAD4 exome AF: 0.149 AC: 217248 AN: 1461616 Hom.: 17197 Cov.: 35 AF XY: 0.149 AC XY: 108072 AN XY: 727138

Gnomad4 AFR exome AF: 0.0226

Gnomad4 AMR exome AF: 0.0898

Gnomad4 ASJ exome AF: 0.211

Gnomad4 EAS exome AF: 0.0746

Gnomad4 SAS exome AF: 0.113

Gnomad4 FIN exome AF: 0.140

Gnomad4 NFE exome AF: 0.159

Gnomad4 OTH exome AF: 0.145

GnomAD4 genome AF: 0.115 AC: 17475 AN: 152162 Hom.: 1253 Cov.: 31 AF XY: 0.114 AC XY: 8458 AN XY: 74370

Gnomad4 AFR AF: 0.0292

Gnomad4 AMR AF: 0.117

Gnomad4 ASJ AF: 0.201

Gnomad4 EAS AF: 0.0874

Gnomad4 SAS AF: 0.102

Gnomad4 FIN AF: 0.141

Gnomad4 NFE AF: 0.161

Gnomad4 OTH AF: 0.124

Alfa AF: 0.157 Hom.: 2746

Bravo AF: 0.108

Asia WGS AF: 0.0950 AC: 330 AN: 3478

EpiCase AF: 0.164

EpiControl AF: 0.166

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Sep 04, 2013

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.8
DANN	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs2307418; hg19: chr1-161200586;