rs12721615

Variant names:

• chr3-119818376-A-G
• rs12721615
• NM_003889.4:c.*1164A>G

Variant summary

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

The NM_003889.4(NR1I2):​c.*1164A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00978 in 985,372 control chromosomes in the GnomAD database, including 58 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 0.0055 (6 hom., cov: 32)
  • Exomes 𝑓: 0.011 (52 hom.)
• Consequence: NR1I2 NM_003889.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.530
• Publications: 2 publications found

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]

NR1I2 Gene-Disease associations (from GenCC):

• pediatric lymphoma

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1I2	NM_003889.4	c.*1164A>G		3_prime_UTR_variant	Exon 9 of 9	ENST00000393716.8	NP_003880.3
NR1I2	NM_022002.3	c.*1164A>G		3_prime_UTR_variant	Exon 9 of 9		NP_071285.1
NR1I2	NM_033013.3	c.*1164A>G		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.*1164A>G		3_prime_UTR_variant	Exon 9 of 9	1	NM_003889.4	ENSP00000377319.3
NR1I2	ENST00000337940.4	c.*1164A>G		3_prime_UTR_variant	Exon 9 of 9	1		ENSP00000336528.4
NR1I2	ENST00000466380.6	c.*1164A>G		3_prime_UTR_variant	Exon 9 of 9	1		ENSP00000420297.2
NR1I2	ENST00000493757.1	n.2601A>G		non_coding_transcript_exon_variant	Exon 6 of 6	2

Frequencies

GnomAD3 genomes AF: 0.00553 AC: 841 AN: 152214 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.000960

GnomAD4 exome AF: 0.0106 AC: 8794 AN: 833040 Hom.: 52 Cov.: 32 AF XY: 0.0106 AC XY: 4068 AN XY: 384682

African (AFR) AF: 0.00108 AC: 17 AN: 15786

American (AMR) AF: 0.00204 AC: 2 AN: 982

Ashkenazi Jewish (ASJ) AF: 0.000582 AC: 3 AN: 5152

East Asian (EAS) AF: 0.00 AC: 0 AN: 3628

South Asian (SAS) AF: 0.00152 AC: 25 AN: 16458

European-Finnish (FIN) AF: 0.0109 AC: 3 AN: 276

Middle Eastern (MID) AF: 0.000617 AC: 1 AN: 1620

European-Non Finnish (NFE) AF: 0.0112 AC: 8529 AN: 761844

Other (OTH) AF: 0.00784 AC: 214 AN: 27294

GnomAD4 genome AF: 0.00552 AC: 841 AN: 152332 Hom.: 6 Cov.: 32 AF XY: 0.00516 AC XY: 384 AN XY: 74490

African (AFR) AF: 0.00173 AC: 72 AN: 41572

American (AMR) AF: 0.00163 AC: 25 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00165 AC: 8 AN: 4834

European-Finnish (FIN) AF: 0.00471 AC: 50 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0101 AC: 684 AN: 68038

Other (OTH) AF: 0.000950 AC: 2 AN: 2106

Alfa AF: 0.00779 Hom.: 11

Bravo AF: 0.00549

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	5.6
DANN	Benign	0.90
PhyloP100		0.53

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

Other links and lift over

dbSNP: rs12721615; hg19: chr3-119537223;