1-161229713-G-C

Variant names:

• chr1-161229713-G-C
• ENST00000428574.6:c.992C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001077469.3(NR1I3):​c.992C>G​(p.Pro331Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/15 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P331L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NR1I3 NM_001077469.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.624

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 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=0.08747825).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1I3	NM_005122.5	c.*84C>G		3_prime_UTR_variant	Exon 9 of 9	ENST00000367983.9	NP_005113.1
TOMM40L	NM_032174.6	c.*618G>C		3_prime_UTR_variant	Exon 10 of 10	ENST00000367988.8	NP_115550.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR1I3	ENST00000367983	c.*84C>G		3_prime_UTR_variant	Exon 9 of 9	1	NM_005122.5	ENSP00000356962.5
TOMM40L	ENST00000367988.8	c.*618G>C		3_prime_UTR_variant	Exon 10 of 10	2	NM_032174.6	ENSP00000356967.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	2.0
DANN	Benign	0.45
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.42	T;T;T;T;T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.087	T;T;T;T;T;T;T
MetaSVM	Benign	-0.87	T
PROVEAN	Benign	0.60	N;N;N;N;N;N;N
REVEL	Benign	0.11
Sift	Pathogenic	0.0	D;D;D;D;D;D;D
Vest4		0.13
MutPred		0.43		.;.;.;.;Gain of methylation at P331 (P = 0.0121);.;.;
MVP		0.51
ClinPred		0.12	T
GERP RS		-3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-161199503;