1-161231366-G-A

Variant names:

• chr1-161231366-G-A
• rs544805520
• ENST00000502985.5:c.347C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000502985.5(NR1I3):​c.347C>T​(p.Ala116Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000691 in 1,563,456 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A116A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000072 (2 hom.)
• Consequence: NR1I3 ENST00000502985.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.255

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]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01935941).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1I3	NM_005122.5	c.657C>T	p.Cys219Cys	synonymous_variant	Exon 6 of 9	ENST00000367983.9	NP_005113.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR1I3	ENST00000367983.9	c.657C>T	p.Cys219Cys	synonymous_variant	Exon 6 of 9	1	NM_005122.5	ENSP00000356962.5

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000713 AC: 15 AN: 210490 AF XY: 0.0000879

Gnomad AFR exome AF: 0.000128

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000508

Gnomad NFE exome AF: 0.0000198

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000716 AC: 101 AN: 1411172 Hom.: 2 Cov.: 34 AF XY: 0.0000787 AC XY: 55 AN XY: 698472

Gnomad4 AFR exome AF: 0.0000647 AC: 2 AN: 30904

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 32974

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 23076

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39278

Gnomad4 SAS exome AF: 0.000800 AC: 63 AN: 78790

Gnomad4 FIN exome AF: 0.0000191 AC: 1 AN: 52246

Gnomad4 NFE exome AF: 0.0000238 AC: 26 AN: 1090304

Gnomad4 Remaining exome AF: 0.000155 AC: 9 AN: 58096

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74456

Gnomad4 AFR AF: 0.0000241 AC: 0.0000240639 AN: 0.0000240639

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000193 AC: 0.000192753 AN: 0.000192753

Gnomad4 SAS AF: 0.000828 AC: 0.000828157 AN: 0.000828157

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000147 AC: 0.000014702 AN: 0.000014702

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000540 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000659 AC: 8

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 07, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Uncertain	0.060
CADD	Benign	6.7
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0098	T;T;T;T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.41	.;.;T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.019	T;T;T;T
MetaSVM	Benign	-0.94	T
PROVEAN	Benign	-0.43	N;N;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.048	D;D;D;D
Sift4G	Uncertain	0.014	D;T;T;D
Polyphen		0.0050	B;B;B;B
Vest4		0.17
MutPred		0.24		.;Loss of disorder (P = 0.0906);Loss of disorder (P = 0.0906);.;
MVP		0.53
ClinPred		0.019	T
GERP RS		-5.2
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs544805520; hg19: chr1-161201156;