rs12721607

Positions:

• chr3-119807356-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_003889.4(NR1I2):​c.106G>A​(p.Gly36Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0214 in 1,614,186 control chromosomes in the GnomAD database, including 420 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.014 (23 hom., cov: 32)
  • Exomes 𝑓: 0.022 (397 hom.)
• Consequence: NR1I2 NM_003889.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.50

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039529204).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0144 (2188/152330) while in subpopulation NFE AF= 0.0256 (1743/68026). AF 95% confidence interval is 0.0246. There are 23 homozygotes in gnomad4. There are 953 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR1I2	NM_003889.4	c.106G>A	p.Gly36Arg	missense_variant	2/9	ENST00000393716.8
NR1I2	NM_022002.3	c.223G>A	p.Gly75Arg	missense_variant	2/9
NR1I2	NM_033013.3	c.106G>A	p.Gly36Arg	missense_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR1I2	ENST00000393716.8	c.106G>A	p.Gly36Arg	missense_variant	2/9	1	NM_003889.4	P2
NR1I2	ENST00000337940.4	c.223G>A	p.Gly75Arg	missense_variant	2/9	1		A2
NR1I2	ENST00000466380.6	c.106G>A	p.Gly36Arg	missense_variant	2/9	1		A2
NR1I2	ENST00000474090.1	n.394G>A		non_coding_transcript_exon_variant	2/3	1

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2188 AN: 152212 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.00446

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.0126

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0256

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.0138 AC: 3461 AN: 251482 Hom.: 39 AF XY: 0.0137 AC XY: 1858 AN XY: 135916

Gnomad AFR exome AF: 0.00412

Gnomad AMR exome AF: 0.00535

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00402

Gnomad FIN exome AF: 0.0122

Gnomad NFE exome AF: 0.0240

Gnomad OTH exome AF: 0.0142

GnomAD4 exome AF: 0.0221 AC: 32297 AN: 1461856 Hom.: 397 Cov.: 32 AF XY: 0.0216 AC XY: 15704 AN XY: 727230

Gnomad4 AFR exome AF: 0.00326

Gnomad4 AMR exome AF: 0.00575

Gnomad4 ASJ exome AF: 0.000574

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00463

Gnomad4 FIN exome AF: 0.0130

Gnomad4 NFE exome AF: 0.0267

Gnomad4 OTH exome AF: 0.0182

GnomAD4 genome AF: 0.0144 AC: 2188 AN: 152330 Hom.: 23 Cov.: 32 AF XY: 0.0128 AC XY: 953 AN XY: 74506

Gnomad4 AFR AF: 0.00445

Gnomad4 AMR AF: 0.00562

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.0126

Gnomad4 NFE AF: 0.0256

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.0218 Hom.: 64

Bravo AF: 0.0136

TwinsUK AF: 0.0289 AC: 107

ALSPAC AF: 0.0267 AC: 103

ESP6500AA AF: 0.00545 AC: 24

ESP6500EA AF: 0.0249 AC: 214

ExAC AF: 0.0146 AC: 1774

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0231

EpiControl AF: 0.0191

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	.;.;.;.;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.66	T;T;T;T;T
MetaRNN	Benign	0.0040	T;T;T;T;T
MetaSVM	Uncertain	-0.080	T
MutationAssessor	Benign	1.2	.;.;.;L;L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.3	N;N;N;.;.
REVEL	Benign	0.23
Sift	Uncertain	0.0090	D;D;D;.;.
Sift4G	Uncertain	0.051	T;T;T;.;.
Vest4		0.086
MutPred		0.28		.;.;Gain of solvent accessibility (P = 0.0456);.;.;
MPC		0.30
ClinPred		0.0086	T
GERP RS		2.9
Varity_R		0.049
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12721607; hg19: chr3-119526203;