chr1-161229877-T-A

Position:

• chr1-161229877-T-A

Variant summary

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

The NM_005122.5(NR1I3):​c.967A>T​(p.Asn323Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NR1I3 NM_005122.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.15

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]

NR1I3 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR1I3	NM_005122.5	c.967A>T	p.Asn323Tyr	missense_variant	9/9	ENST00000367983.9	NP_005113.1
TOMM40L	NM_032174.6	c.*782T>A		3_prime_UTR_variant	10/10	ENST00000367988.8	NP_115550.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR1I3	ENST00000367983.9	c.967A>T	p.Asn323Tyr	missense_variant	9/9	1	NM_005122.5	ENSP00000356962.5
TOMM40L	ENST00000367988.8	c.*782T>A		3_prime_UTR_variant	10/10	2	NM_032174.6	ENSP00000356967.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 07, 2024

The c.967A>T (p.N323Y) alteration is located in exon 9 (coding exon 8) of the NR1I3 gene. This alteration results from a A to T substitution at nucleotide position 967, causing the asparagine (N) at amino acid position 323 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.71	.;.;D;.;.;.;.;.;.;.
Eigen	Benign	0.0011
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.81	T;T;T;T;T;T;T;T;T;.
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.68	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Uncertain	2.7	.;.;M;.;.;.;.;.;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-5.1	D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 0.99	.;.;D;.;.;.;D;.;.;.
Vest4		0.43
MutPred		0.70		.;.;Gain of catalytic residue at I326 (P = 0.0536);.;.;.;.;.;.;.;
MVP		0.98
MPC		0.75
ClinPred		0.92	D
GERP RS		3.0
Varity_R		0.27
gMVP		0.52

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: chr1-161199667;