NM_003889.4:c.331+648C>T

Variant names:

• chr3-119810842-C-T
• rs2472681
• NM_003889.4:c.331+648C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003889.4(NR1I2):​c.331+648C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.59 in 152,000 control chromosomes in the GnomAD database, including 28,378 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 0.59 (28378 hom., cov: 32)
• Consequence: NR1I2 NM_003889.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.936
• Publications: 7 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.693 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003889.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR1I2	NM_003889.4	MANE Select	c.331+648C>T		intron	N/A	NP_003880.3
	NR1I2	NM_022002.3		c.448+648C>T		intron	N/A	NP_071285.1
	NR1I2	NM_033013.3		c.331+648C>T		intron	N/A	NP_148934.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR1I2	ENST00000393716.8	TSL:1 MANE Select	c.331+648C>T		intron	N/A	ENSP00000377319.3
	NR1I2	ENST00000337940.4	TSL:1	c.448+648C>T		intron	N/A	ENSP00000336528.4
	NR1I2	ENST00000466380.6	TSL:1	c.331+648C>T		intron	N/A	ENSP00000420297.2

Frequencies

GnomAD3 genomes AF: 0.591 AC: 89707 AN: 151882 Hom.: 28387 Cov.: 32

Gnomad AFR AF: 0.339

Gnomad AMI AF: 0.781

Gnomad AMR AF: 0.695

Gnomad ASJ AF: 0.690

Gnomad EAS AF: 0.672

Gnomad SAS AF: 0.587

Gnomad FIN AF: 0.643

Gnomad MID AF: 0.640

Gnomad NFE AF: 0.698

Gnomad OTH AF: 0.611

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.590 AC: 89721 AN: 152000 Hom.: 28378 Cov.: 32 AF XY: 0.592 AC XY: 44010 AN XY: 74310

African (AFR) AF: 0.339 AC: 14041 AN: 41452

American (AMR) AF: 0.694 AC: 10601 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.690 AC: 2394 AN: 3472

East Asian (EAS) AF: 0.673 AC: 3468 AN: 5154

South Asian (SAS) AF: 0.587 AC: 2828 AN: 4814

European-Finnish (FIN) AF: 0.643 AC: 6790 AN: 10564

Middle Eastern (MID) AF: 0.627 AC: 183 AN: 292

European-Non Finnish (NFE) AF: 0.698 AC: 47414 AN: 67946

Other (OTH) AF: 0.610 AC: 1290 AN: 2114

Alfa AF: 0.652 Hom.: 12899

Bravo AF: 0.586

Asia WGS AF: 0.610 AC: 2123 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.2
DANN	Benign	0.53
PhyloP100		-0.94
Mutation Taster		=100/0	polymorphism (auto)

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: rs2472681; hg19: chr3-119529689;