rs12721600

chr3-119812709-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_003889.4(NR1I2):c.543C>T(p.Gly181=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,614,126 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0026 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (29 hom.)
• Consequence: NR1I2 NM_003889.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.475

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 3-119812709-C-T is Benign according to our data. Variant chr3-119812709-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2654059.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.475 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR1I2	NM_003889.4	c.543C>T	p.Gly181=	synonymous_variant	5/9	ENST00000393716.8
NR1I2	NM_022002.3	c.660C>T	p.Gly220=	synonymous_variant	5/9
NR1I2	NM_033013.3	c.520-88C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR1I2	ENST00000393716.8	c.543C>T	p.Gly181=	synonymous_variant	5/9	1	NM_003889.4	P2
NR1I2	ENST00000337940.4	c.660C>T	p.Gly220=	synonymous_variant	5/9	1		A2
NR1I2	ENST00000466380.6	c.520-88C>T		intron_variant		1		A2
NR1I2	ENST00000493757.1	n.675C>T		non_coding_transcript_exon_variant	2/6	2

Frequencies

GnomAD3 genomes AF: 0.00263 AC: 401 AN: 152218 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00310 AC: 780 AN: 251374 Hom.: 9 AF XY: 0.00292 AC XY: 397 AN XY: 135876

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0293

Gnomad NFE exome AF: 0.00111

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00142 AC: 2069 AN: 1461790 Hom.: 29 Cov.: 32 AF XY: 0.00140 AC XY: 1018 AN XY: 727198

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0296

Gnomad4 NFE exome AF: 0.000369

Gnomad4 OTH exome AF: 0.00128

GnomAD4 genome AF: 0.00263 AC: 401 AN: 152336 Hom.: 6 Cov.: 32 AF XY: 0.00360 AC XY: 268 AN XY: 74492

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0283

Gnomad4 NFE AF: 0.00143

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00148 Hom.: 1

Bravo AF: 0.000280

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2022

NR1I2: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	3.2
Dann	Benign	0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs12721600; hg19: chr3-119531556;