rs12721612

Positions:

• chr3-119815018-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003889.4(NR1I2):​c.834G>A​(p.Gly278Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 1,614,184 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (18 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (30 hom.)
• Consequence: NR1I2 NM_003889.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.949

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 3-119815018-G-A is Benign according to our data. Variant chr3-119815018-G-A is described in ClinVar as [Benign]. Clinvar id is 788396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.949 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.01 (1529/152302) while in subpopulation AFR AF= 0.0351 (1460/41578). AF 95% confidence interval is 0.0336. There are 18 homozygotes in gnomad4. There are 692 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR1I2	NM_003889.4	c.834G>A	p.Gly278Gly	synonymous_variant	6/9	ENST00000393716.8	NP_003880.3
NR1I2	NM_022002.3	c.951G>A	p.Gly317Gly	synonymous_variant	6/9		NP_071285.1
NR1I2	NM_033013.3	c.723G>A	p.Gly241Gly	synonymous_variant	6/9		NP_148934.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR1I2	ENST00000393716.8	c.834G>A	p.Gly278Gly	synonymous_variant	6/9	1	NM_003889.4	ENSP00000377319.3
NR1I2	ENST00000337940.4	c.951G>A	p.Gly317Gly	synonymous_variant	6/9	1		ENSP00000336528.4
NR1I2	ENST00000466380.6	c.723G>A	p.Gly241Gly	synonymous_variant	6/9	1		ENSP00000420297.2
NR1I2	ENST00000493757.1	n.966G>A		non_coding_transcript_exon_variant	3/6	2

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1528 AN: 152184 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0352

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.00265 AC: 666 AN: 251376 Hom.: 10 AF XY: 0.00194 AC XY: 263 AN XY: 135896

Gnomad AFR exome AF: 0.0368

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.00106 AC: 1543 AN: 1461882 Hom.: 30 Cov.: 35 AF XY: 0.000914 AC XY: 665 AN XY: 727246

Gnomad4 AFR exome AF: 0.0378

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000378

Gnomad4 OTH exome AF: 0.00219

GnomAD4 genome AF: 0.0100 AC: 1529 AN: 152302 Hom.: 18 Cov.: 32 AF XY: 0.00929 AC XY: 692 AN XY: 74466

Gnomad4 AFR AF: 0.0351

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.00260 Hom.: 11

Bravo AF: 0.0119

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 18, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	4.8
DANN	Benign	0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs12721612; hg19: chr3-119533865;