rs12721611

Variant names:

• chr3-119811699-T-C
• rs12721611
• NM_003889.4:c.492T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003889.4(NR1I2):​c.492T>C​(p.Thr164Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00324 in 1,612,596 control chromosomes in the GnomAD database, including 150 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (79 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (71 hom.)
• Consequence: NR1I2 NM_003889.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.170
• Publications: 6 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 3-119811699-T-C is Benign according to our data. Variant chr3-119811699-T-C is described in ClinVar as Benign. ClinVar VariationId is 775899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.17 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0569 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.492T>C	p.Thr164Thr	synonymous	Exon 4 of 9	NP_003880.3
	NR1I2	NM_022002.3		c.609T>C	p.Thr203Thr	synonymous	Exon 4 of 9	NP_071285.1
	NR1I2	NM_033013.3		c.492T>C	p.Thr164Thr	synonymous	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.492T>C	p.Thr164Thr	synonymous	Exon 4 of 9	ENSP00000377319.3
	NR1I2	ENST00000337940.4	TSL:1	c.609T>C	p.Thr203Thr	synonymous	Exon 4 of 9	ENSP00000336528.4
	NR1I2	ENST00000466380.6	TSL:1	c.492T>C	p.Thr164Thr	synonymous	Exon 4 of 9	ENSP00000420297.2

Frequencies

GnomAD3 genomes AF: 0.0176 AC: 2675 AN: 152176 Hom.: 78 Cov.: 32

Gnomad AFR AF: 0.0588

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.00456 AC: 1127 AN: 246910 AF XY: 0.00317

Gnomad AFR exome AF: 0.0586

Gnomad AMR exome AF: 0.00479

Gnomad ASJ exome AF: 0.000301

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000152

Gnomad OTH exome AF: 0.00232

GnomAD4 exome AF: 0.00174 AC: 2541 AN: 1460302 Hom.: 71 Cov.: 31 AF XY: 0.00143 AC XY: 1039 AN XY: 726260

African (AFR) AF: 0.0566 AC: 1892 AN: 33452

American (AMR) AF: 0.00528 AC: 235 AN: 44538

Ashkenazi Jewish (ASJ) AF: 0.000422 AC: 11 AN: 26076

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.0000932 AC: 8 AN: 85866

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5766

European-Non Finnish (NFE) AF: 0.000141 AC: 157 AN: 1111268

Other (OTH) AF: 0.00385 AC: 232 AN: 60324

GnomAD4 genome AF: 0.0176 AC: 2682 AN: 152294 Hom.: 79 Cov.: 32 AF XY: 0.0170 AC XY: 1265 AN XY: 74492

African (AFR) AF: 0.0588 AC: 2443 AN: 41550

American (AMR) AF: 0.0132 AC: 202 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68020

Other (OTH) AF: 0.0147 AC: 31 AN: 2112

Alfa AF: 0.00773 Hom.: 60

Bravo AF: 0.0199

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	11
DANN	Benign	0.63
PhyloP100		0.17
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
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: rs12721611; hg19: chr3-119530546;