rs35761343

Positions:

chr3-119815779-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_003889.4(NR1I2):c.1108G>A(p.Ala370Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000802 in 1,613,732 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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 0.0043 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00043 ( 7 hom. )

Consequence

NR1I2
NM_003889.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.10

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00626415).

BS1

Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000432 (632/1461406) while in subpopulation AFR AF= 0.0162 (541/33470). AF 95% confidence interval is 0.015. There are 7 homozygotes in gnomad4_exome. There are 284 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NR1I2	NM_003889.4 linkuse as main transcript	c.1108G>A	p.Ala370Thr	missense_variant	8/9	ENST00000393716.8	NP_003880.3
NR1I2	NM_022002.3 linkuse as main transcript	c.1225G>A	p.Ala409Thr	missense_variant	8/9		NP_071285.1
NR1I2	NM_033013.3 linkuse as main transcript	c.997G>A	p.Ala333Thr	missense_variant	8/9		NP_148934.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR1I2	ENST00000393716.8 linkuse as main transcript	c.1108G>A	p.Ala370Thr	missense_variant	8/9	1	NM_003889.4	ENSP00000377319	P2	O75469-1
NR1I2	ENST00000337940.4 linkuse as main transcript	c.1225G>A	p.Ala409Thr	missense_variant	8/9	1		ENSP00000336528	A2	O75469-7
NR1I2	ENST00000466380.6 linkuse as main transcript	c.997G>A	p.Ala333Thr	missense_variant	8/9	1		ENSP00000420297	A2	O75469-4
NR1I2	ENST00000493757.1 linkuse as main transcript	n.1240G>A		non_coding_transcript_exon_variant	5/6	2

Frequencies

GnomAD3 genomes

AF:

0.00435

AC:

662

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0154

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000981

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00106

AC:

265

AN:

249384

Hom.:

AF XY:

0.000764

AC XY:

103

AN XY:

134846

show subpopulations

Gnomad AFR exome

AF:

0.0153

Gnomad AMR exome

AF:

0.000348

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.0000659

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000432

AC:

632

AN:

1461406

Hom.:

Cov.:

AF XY:

0.000391

AC XY:

284

AN XY:

726920

show subpopulations

Gnomad4 AFR exome

AF:

0.0162

Gnomad4 AMR exome

AF:

0.000493

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000465

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.000795

GnomAD4 genome

AF:

0.00435

AC:

662

AN:

152326

Hom.:

Cov.:

AF XY:

0.00395

AC XY:

294

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0154

Gnomad4 AMR

AF:

0.000980

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00236

Alfa

AF:

0.000942

Hom.:

Bravo

AF:

0.00532

ESP6500AA

AF:

0.0150

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00145

AC:

176

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

.;.;.;.;D

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.85

T;T;D;T;T

MetaRNN

Benign

0.0063

T;T;T;T;T

MetaSVM

Uncertain

0.10

MutationAssessor

Benign

1.4

.;.;.;.;L

MutationTaster

Benign

1.0

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-2.5

N;N;N;.;.

REVEL

Uncertain

0.31

Sift

Benign

0.057

T;D;D;.;.

Sift4G

Benign

0.098

T;T;T;.;.

Polyphen

0.99

.;.;.;.;D

Vest4

0.24

MVP

0.88

MPC

0.23

ClinPred

0.045

GERP RS

3.1

Varity_R

0.32

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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