Variant chr3-119807356-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -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. 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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

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

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 links:

ENSG00000285585 (HGNC:):

ENSG00000285585 links:

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ACMG classification

Classification made for transcript

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 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

GnomAD3 exomes

AF:

0.0138

AC:

3461

AN:

251482

Hom.:

AF XY:

0.0137

AC XY:

1858

AN XY:

135916

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 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.:

AF XY:

0.0216

AC XY:

15704

AN XY:

727230

show subpopulations

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.:

Cov.:

AF XY:

0.0128

AC XY:

953

AN XY:

74506

show subpopulations

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.:

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

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

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over