rs12721607

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.014 ( 23 hom., cov: 32)

Exomes 𝑓: 0.022 ( 397 hom. )

Consequence

NR1I2
NM_003889.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.50

Publications

38 publications found

Variant links:

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

NR1I2 links:

ENSG00000285585 (HGNC:):

ENSG00000285585 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1I2	NM_003889.4 link	c.106G>A	p.Gly36Arg	missense_variant	Exon 2 of 9	ENST00000393716.8	NP_003880.3	O75469-1
NR1I2	NM_022002.3 link	c.223G>A	p.Gly75Arg	missense_variant	Exon 2 of 9		NP_071285.1	O75469-7F1D8P9
NR1I2	NM_033013.3 link	c.106G>A	p.Gly36Arg	missense_variant	Exon 2 of 9		NP_148934.1	O75469-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR1I2	ENST00000393716.8 link	c.106G>A	p.Gly36Arg	missense_variant	Exon 2 of 9	1	NM_003889.4	ENSP00000377319.3		O75469-1J3KPQ3
ENSG00000285585	ENST00000648112.1 link	c.*129G>A		3_prime_UTR_variant	Exon 18 of 18			ENSP00000497876.1

Frequencies

GnomAD3 genomes

AF:

0.0144

AC:

2188

AN:

152212

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0138

AC:

3461

AN:

251482

AF XY:

0.0137

show subpopulations

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 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.:

AF XY:

0.0216

AC XY:

15704

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00326

AC:

109

AN:

33480

American (AMR)

AF:

0.00575

AC:

257

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000574

AC:

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.00463

AC:

399

AN:

86258

European-Finnish (FIN)

AF:

0.0130

AC:

697

AN:

53414

Middle Eastern (MID)

AF:

0.00329

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0267

AC:

29696

AN:

1111980

Other (OTH)

AF:

0.0182

AC:

1101

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

1771

3542

5312

7083

8854

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1100

2200

3300

4400

5500

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0144

AC:

2188

AN:

152330

Hom.:

Cov.:

AF XY:

0.0128

AC XY:

953

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.00445

AC:

185

AN:

41580

American (AMR)

AF:

0.00562

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000772

AC:

AN:

5184

South Asian (SAS)

AF:

0.00352

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0126

AC:

134

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0256

AC:

1743

AN:

68026

Other (OTH)

AF:

0.00804

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

118

236

353

471

589

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0208

Hom.:

Bravo

AF:

0.0136

TwinsUK

AF:

0.0289

AC:

107

ALSPAC

AF:

0.0267

AC:

103

ESP6500AA

AF:

0.00545

AC:

ESP6500EA

AF:

0.0249

AC:

214

ExAC

AF:

0.0146

AC:

1774

Asia WGS

AF:

0.00260

AC:

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

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

.;.;.;.;T

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.66

T;T;T;T;T

MetaRNN

Benign

0.0040

T;T;T;T;T

MetaSVM

Uncertain

-0.080

MutationAssessor

Benign

1.2

.;.;.;L;L

PhyloP100

1.5

PrimateAI

Benign

0.29

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

GERP RS

2.9

Varity_R

0.049

gMVP

0.53

Mutation Taster

=84/16

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over