rs3732358

Variant names:

• chr3-119817227-G-A
• rs3732358
• NM_003889.4:c.*15G>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003889.4(NR1I2):​c.*15G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00533 in 1,613,280 control chromosomes in the GnomAD database, including 258 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.023 (126 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (132 hom.)
• Consequence: NR1I2 NM_003889.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.165

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0778 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1I2	NM_003889.4	c.*15G>A		3_prime_UTR_variant	Exon 9 of 9	ENST00000393716.8	NP_003880.3
NR1I2	NM_022002.3	c.*15G>A		3_prime_UTR_variant	Exon 9 of 9		NP_071285.1
NR1I2	NM_033013.3	c.*15G>A		3_prime_UTR_variant	Exon 9 of 9		NP_148934.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR1I2	ENST00000393716.8	c.*15G>A		3_prime_UTR_variant	Exon 9 of 9	1	NM_003889.4	ENSP00000377319.3
NR1I2	ENST00000337940.4	c.*15G>A		3_prime_UTR_variant	Exon 9 of 9	1		ENSP00000336528.4
NR1I2	ENST00000466380.6	c.*15G>A		3_prime_UTR_variant	Exon 9 of 9	1		ENSP00000420297.2
NR1I2	ENST00000493757.1	n.1452G>A		non_coding_transcript_exon_variant	Exon 6 of 6	2

Frequencies

GnomAD3 genomes AF: 0.0234 AC: 3553 AN: 152110 Hom.: 123 Cov.: 32

Gnomad AFR AF: 0.0800

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00766

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0100

Gnomad SAS AF: 0.00436

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.00692 AC: 1734 AN: 250676 Hom.: 58 AF XY: 0.00556 AC XY: 754 AN XY: 135586

Gnomad AFR exome AF: 0.0848

Gnomad AMR exome AF: 0.00298

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00228

Gnomad SAS exome AF: 0.00500

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000378

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00345 AC: 5034 AN: 1461052 Hom.: 132 Cov.: 30 AF XY: 0.00321 AC XY: 2336 AN XY: 726862

Gnomad4 AFR exome AF: 0.0813

Gnomad4 AMR exome AF: 0.00376

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0261

Gnomad4 SAS exome AF: 0.00524

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000192

Gnomad4 OTH exome AF: 0.00676

GnomAD4 genome AF: 0.0234 AC: 3569 AN: 152228 Hom.: 126 Cov.: 32 AF XY: 0.0231 AC XY: 1723 AN XY: 74430

Gnomad4 AFR AF: 0.0801

Gnomad4 AMR AF: 0.00765

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0100

Gnomad4 SAS AF: 0.00437

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.00377 Hom.: 25

Bravo AF: 0.0269

Asia WGS AF: 0.0150 AC: 51 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.5
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3732358; hg19: chr3-119536074;