NM_003889.4:c.-22-11008A>G

Variant names:

• chr3-119796221-A-G
• rs16830505
• NM_003889.4:c.-22-11008A>G

Variant summary

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

The NM_003889.4(NR1I2):​c.-22-11008A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 152,164 control chromosomes in the GnomAD database, including 2,290 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 0.15 (2290 hom., cov: 32)
• Consequence: NR1I2 NM_003889.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.32
• Publications: 8 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

ENSG00000285585 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.277 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1I2	NM_003889.4	c.-22-11008A>G		intron_variant	Intron 1 of 8	ENST00000393716.8	NP_003880.3
NR1I2	NM_022002.3	c.96-11008A>G		intron_variant	Intron 1 of 8		NP_071285.1
NR1I2	NM_033013.3	c.-22-11008A>G		intron_variant	Intron 1 of 8		NP_148934.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR1I2	ENST00000393716.8	c.-22-11008A>G		intron_variant	Intron 1 of 8	1	NM_003889.4	ENSP00000377319.3
ENSG00000285585	ENST00000648112.1	c.*2-11008A>G		intron_variant	Intron 17 of 17			ENSP00000497876.1

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23123 AN: 152046 Hom.: 2289 Cov.: 32

Gnomad AFR AF: 0.281

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.0937

Gnomad ASJ AF: 0.154

Gnomad EAS AF: 0.0150

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.0693

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.161

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

GnomAD4 genome AF: 0.152 AC: 23152 AN: 152164 Hom.: 2290 Cov.: 32 AF XY: 0.146 AC XY: 10892 AN XY: 74388

African (AFR) AF: 0.281 AC: 11676 AN: 41496

American (AMR) AF: 0.0935 AC: 1430 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.154 AC: 536 AN: 3472

East Asian (EAS) AF: 0.0151 AC: 78 AN: 5180

South Asian (SAS) AF: 0.104 AC: 501 AN: 4818

European-Finnish (FIN) AF: 0.0693 AC: 735 AN: 10610

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.114 AC: 7741 AN: 67976

Other (OTH) AF: 0.160 AC: 338 AN: 2110

Alfa AF: 0.126 Hom.: 1187

Bravo AF: 0.158

Asia WGS AF: 0.0780 AC: 270 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.4
DANN	Benign	0.65
PhyloP100		1.3
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: rs16830505; hg19: chr3-119515068;