rs59371185

chr3-119807302-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_003889.4(NR1I2):c.52G>A(p.Glu18Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000769 in 1,614,242 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0041 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (5 hom.)
• Consequence: NR1I2 NM_003889.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.06

Genes affected

NR1I2 (HGNC:7968): (nuclear receptor subfamily 1 group I member 2) This gene product belongs to the nuclear receptor superfamily, members of which are transcription factors characterized by a ligand-binding domain and a DNA-binding domain. The encoded protein is a transcriptional regulator of the cytochrome P450 gene CYP3A4, binding to the response element of the CYP3A4 promoter as a heterodimer with the 9-cis retinoic acid receptor RXR. It is activated by a range of compounds that induce CYP3A4, including dexamethasone and rifampicin. Several alternatively spliced transcripts encoding different isoforms, some of which use non-AUG (CUG) translation initiation codon, have been described for this gene. Additional transcript variants exist, however, they have not been fully characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005196452).
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR1I2	NM_003889.4	c.52G>A	p.Glu18Lys	missense_variant	2/9	ENST00000393716.8
NR1I2	NM_022002.3	c.169G>A	p.Glu57Lys	missense_variant	2/9
NR1I2	NM_033013.3	c.52G>A	p.Glu18Lys	missense_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR1I2	ENST00000393716.8	c.52G>A	p.Glu18Lys	missense_variant	2/9	1	NM_003889.4	P2
NR1I2	ENST00000337940.4	c.169G>A	p.Glu57Lys	missense_variant	2/9	1		A2
NR1I2	ENST00000466380.6	c.52G>A	p.Glu18Lys	missense_variant	2/9	1		A2
NR1I2	ENST00000474090.1	n.340G>A		non_coding_transcript_exon_variant	2/3	1

Frequencies

GnomAD3 genomes AF: 0.00414 AC: 630 AN: 152234 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00109 AC: 273 AN: 251484 Hom.: 2 AF XY: 0.000765 AC XY: 104 AN XY: 135922

Gnomad AFR exome AF: 0.0158

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000419 AC: 612 AN: 1461890 Hom.: 5 Cov.: 32 AF XY: 0.000371 AC XY: 270 AN XY: 727246

Gnomad4 AFR exome AF: 0.0157

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000828

GnomAD4 genome AF: 0.00414 AC: 630 AN: 152352 Hom.: 4 Cov.: 32 AF XY: 0.00380 AC XY: 283 AN XY: 74500

Gnomad4 AFR AF: 0.0146

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000801 Hom.: 0

Bravo AF: 0.00510

ESP6500AA AF: 0.0138 AC: 61

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00145 AC: 176

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	0.30
Dann	Benign	0.96
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.54	T;T;T;T;T
MetaRNN	Benign	0.0052	T;T;T;T;T
MetaSVM	Benign	-0.80	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.74	N;N;N;.;.
REVEL	Benign	0.18
Sift	Benign	0.30	T;T;T;.;.
Sift4G	Benign	0.40	T;T;T;.;.
Vest4		0.075
MVP		0.37
MPC		0.092
ClinPred		0.00043	T
GERP RS		1.4
Varity_R		0.021
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs59371185; hg19: chr3-119526149;