1-161229914-C-T

Variant names:

• chr1-161229914-C-T
• rs36017137
• NM_005122.5:c.930G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_005122.5(NR1I3):​c.930G>A​(p.Ala310Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00499 in 1,614,124 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (31 hom.)
• Consequence: NR1I3 NM_005122.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.75
• Publications: 3 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 1-161229914-C-T is Benign according to our data. Variant chr1-161229914-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 167382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.75 with no splicing effect.
• BS2: High AC in GnomAd4 at 546 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.930G>A	p.Ala310Ala	synonymous	Exon 9 of 9	NP_005113.1	Q14994-2
	TOMM40L	NM_032174.6	MANE Select	c.*819C>T		3_prime_UTR	Exon 10 of 10	NP_115550.2
	NR1I3	NM_001077482.3		c.957G>A	p.Ala319Ala	synonymous	Exon 9 of 9	NP_001070950.1	Q14994-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR1I3	ENST00000367983.9	TSL:1 MANE Select	c.930G>A	p.Ala310Ala	synonymous	Exon 9 of 9	ENSP00000356962.5	Q14994-2
	NR1I3	ENST00000367979.6	TSL:1	c.957G>A	p.Ala319Ala	synonymous	Exon 8 of 8	ENSP00000356958.2	Q14994-8
	NR1I3	ENST00000367982.8	TSL:1	c.942G>A	p.Ala314Ala	synonymous	Exon 9 of 9	ENSP00000356961.4	Q14994-1

Frequencies

GnomAD3 genomes AF: 0.00356 AC: 541 AN: 152142 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00554

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00303 AC: 762 AN: 251348 AF XY: 0.00302

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.00556

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.00514

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00514 AC: 7515 AN: 1461864 Hom.: 31 Cov.: 31 AF XY: 0.00500 AC XY: 3638 AN XY: 727230

African (AFR) AF: 0.00212 AC: 71 AN: 33480

American (AMR) AF: 0.00208 AC: 93 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00520 AC: 136 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000406 AC: 35 AN: 86254

European-Finnish (FIN) AF: 0.000243 AC: 13 AN: 53420

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5764

European-Non Finnish (NFE) AF: 0.00614 AC: 6832 AN: 1111996

Other (OTH) AF: 0.00527 AC: 318 AN: 60392

GnomAD4 genome AF: 0.00359 AC: 546 AN: 152260 Hom.: 2 Cov.: 32 AF XY: 0.00356 AC XY: 265 AN XY: 74448

African (AFR) AF: 0.00224 AC: 93 AN: 41554

American (AMR) AF: 0.00275 AC: 42 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00554 AC: 377 AN: 68020

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00475 Hom.: 2

Bravo AF: 0.00394

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	3.2
DANN	Benign	0.77
PhyloP100		-3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs36017137; hg19: chr1-161199704;