3-119815306-C-T

Variant names:

• chr3-119815306-C-T
• rs2276707
• NM_003889.4:c.938-17C>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.938-17C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 1,605,040 control chromosomes in the GnomAD database, including 37,915 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 0.26 (5596 hom., cov: 32)
  • Exomes 𝑓: 0.20 (32319 hom.)
• Consequence: NR1I2 NM_003889.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.184
• Publications: 92 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=-0.79).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.459 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1I2	NM_003889.4	c.938-17C>T		intron_variant	Intron 6 of 8	ENST00000393716.8	NP_003880.3
NR1I2	NM_022002.3	c.1055-17C>T		intron_variant	Intron 6 of 8		NP_071285.1
NR1I2	NM_033013.3	c.827-17C>T		intron_variant	Intron 6 of 8		NP_148934.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR1I2	ENST00000393716.8	c.938-17C>T		intron_variant	Intron 6 of 8	1	NM_003889.4	ENSP00000377319.3
NR1I2	ENST00000337940.4	c.1055-17C>T		intron_variant	Intron 6 of 8	1		ENSP00000336528.4
NR1I2	ENST00000466380.6	c.827-17C>T		intron_variant	Intron 6 of 8	1		ENSP00000420297.2
NR1I2	ENST00000493757.1	n.1070-17C>T		intron_variant	Intron 3 of 5	2

Frequencies

GnomAD3 genomes AF: 0.255 AC: 38789 AN: 151938 Hom.: 5587 Cov.: 32

Gnomad AFR AF: 0.364

Gnomad AMI AF: 0.0789

Gnomad AMR AF: 0.209

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.474

Gnomad SAS AF: 0.290

Gnomad FIN AF: 0.267

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.237

GnomAD2 exomes AF: 0.239 AC: 60162 AN: 251252 AF XY: 0.238

Gnomad AFR exome AF: 0.365

Gnomad AMR exome AF: 0.213

Gnomad ASJ exome AF: 0.184

Gnomad EAS exome AF: 0.465

Gnomad FIN exome AF: 0.258

Gnomad NFE exome AF: 0.185

Gnomad OTH exome AF: 0.224

GnomAD4 exome AF: 0.201 AC: 291353 AN: 1452984 Hom.: 32319 Cov.: 31 AF XY: 0.203 AC XY: 146916 AN XY: 723460

African (AFR) AF: 0.375 AC: 12492 AN: 33320

American (AMR) AF: 0.211 AC: 9436 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 4899 AN: 26068

East Asian (EAS) AF: 0.461 AC: 18284 AN: 39654

South Asian (SAS) AF: 0.277 AC: 23859 AN: 86086

European-Finnish (FIN) AF: 0.256 AC: 13625 AN: 53284

Middle Eastern (MID) AF: 0.234 AC: 1338 AN: 5724

European-Non Finnish (NFE) AF: 0.176 AC: 194058 AN: 1104048

Other (OTH) AF: 0.222 AC: 13362 AN: 60092

GnomAD4 genome AF: 0.255 AC: 38845 AN: 152056 Hom.: 5596 Cov.: 32 AF XY: 0.258 AC XY: 19179 AN XY: 74306

African (AFR) AF: 0.364 AC: 15067 AN: 41446

American (AMR) AF: 0.210 AC: 3207 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 655 AN: 3468

East Asian (EAS) AF: 0.474 AC: 2451 AN: 5168

South Asian (SAS) AF: 0.290 AC: 1397 AN: 4820

European-Finnish (FIN) AF: 0.267 AC: 2820 AN: 10566

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.185 AC: 12599 AN: 67974

Other (OTH) AF: 0.236 AC: 499 AN: 2112

Alfa AF: 0.200 Hom.: 5053

Bravo AF: 0.255

Asia WGS AF: 0.359 AC: 1247 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	5.0
DANN	Benign	0.64
PhyloP100		-0.18
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: rs2276707; hg19: chr3-119534153; COSMIC: COSV61979995; COSMIC: COSV61979995;