rs12721601

Positions:

• chr3-119807211-T-C

Variant summary

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

The NM_003889.4(NR1I2):​c.-22-18T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000484 in 1,606,648 control chromosomes in the GnomAD database, including 5 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 0.0026 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (4 hom.)
• Consequence: NR1I2 NM_003889.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.145

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 (BayesDel_noAF=-0.79).
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR1I2	NM_003889.4	c.-22-18T>C		intron_variant		ENST00000393716.8	NP_003880.3
NR1I2	NM_022002.3	c.96-18T>C		intron_variant			NP_071285.1
NR1I2	NM_033013.3	c.-22-18T>C		intron_variant			NP_148934.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR1I2	ENST00000393716.8	c.-22-18T>C		intron_variant		1	NM_003889.4	ENSP00000377319	P2
NR1I2	ENST00000337940.4	c.96-18T>C		intron_variant		1		ENSP00000336528	A2
NR1I2	ENST00000466380.6	c.-22-18T>C		intron_variant		1		ENSP00000420297	A2
NR1I2	ENST00000474090.1	n.267-18T>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.00257 AC: 391 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00850

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

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: 0.0000735

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.000644 AC: 161 AN: 249880 Hom.: 1 AF XY: 0.000518 AC XY: 70 AN XY: 135164

Gnomad AFR exome AF: 0.00866

Gnomad AMR exome AF: 0.000493

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000263 AC: 383 AN: 1454342 Hom.: 4 Cov.: 30 AF XY: 0.000214 AC XY: 155 AN XY: 723982

Gnomad4 AFR exome AF: 0.00886

Gnomad4 AMR exome AF: 0.000560

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000581

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000362

Gnomad4 OTH exome AF: 0.000865

GnomAD4 genome AF: 0.00259 AC: 394 AN: 152306 Hom.: 1 Cov.: 32 AF XY: 0.00252 AC XY: 188 AN XY: 74476

Gnomad4 AFR AF: 0.00854

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000897 Hom.: 0

Bravo AF: 0.00291

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	12
DANN	Benign	0.84

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: rs12721601; hg19: chr3-119526058;