3-119811572-G-T

Variant names:

• chr3-119811572-G-T
• rs12721608
• NM_003889.4:c.365G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003889.4(NR1I2):​c.365G>T​(p.Arg122Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: NR1I2 NM_003889.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.98
• Publications: 14 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.856

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.365G>T	p.Arg122Leu	missense	Exon 4 of 9	NP_003880.3
	NR1I2	NM_022002.3		c.482G>T	p.Arg161Leu	missense	Exon 4 of 9	NP_071285.1
	NR1I2	NM_033013.3		c.365G>T	p.Arg122Leu	missense	Exon 4 of 9	NP_148934.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR1I2	ENST00000393716.8	TSL:1 MANE Select	c.365G>T	p.Arg122Leu	missense	Exon 4 of 9	ENSP00000377319.3
	NR1I2	ENST00000337940.4	TSL:1	c.482G>T	p.Arg161Leu	missense	Exon 4 of 9	ENSP00000336528.4
	NR1I2	ENST00000466380.6	TSL:1	c.365G>T	p.Arg122Leu	missense	Exon 4 of 9	ENSP00000420297.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000200 AC: 5 AN: 249554 AF XY: 0.0000296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000444

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461332 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726974

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111752

Other (OTH) AF: 0.00 AC: 0 AN: 60360

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		4.0
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.64
MutPred		0.62		Loss of MoRF binding (P = 0.0328)
MVP		0.97
MPC		0.31
ClinPred		0.90	D
GERP RS		4.9
Varity_R		0.27
gMVP		0.81
Mutation Taster		=37/63	disease causing

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: rs12721608; hg19: chr3-119530419;