chr3-119815779-G-A

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.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. 12/21 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 0.0043 ( 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

Publications

24 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:

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=0.00626415).

BS1

Variant frequency is greater than expected in population afr. GnomAdExome4 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 GnomAdExome4. There are 284 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1I2	NM_003889.4 link	c.1108G>A	p.Ala370Thr	missense_variant	Exon 8 of 9	ENST00000393716.8	NP_003880.3	O75469-1
NR1I2	NM_022002.3 link	c.1225G>A	p.Ala409Thr	missense_variant	Exon 8 of 9		NP_071285.1	O75469-7F1D8P9
NR1I2	NM_033013.3 link	c.997G>A	p.Ala333Thr	missense_variant	Exon 8 of 9		NP_148934.1	O75469-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NR1I2	ENST00000393716.8 link	c.1108G>A	p.Ala370Thr	missense_variant	Exon 8 of 9	1	NM_003889.4	ENSP00000377319.3	O75469-1J3KPQ3
NR1I2	ENST00000337940.4 link	c.1225G>A	p.Ala409Thr	missense_variant	Exon 8 of 9	1		ENSP00000336528.4	O75469-7
NR1I2	ENST00000466380.6 link	c.997G>A	p.Ala333Thr	missense_variant	Exon 8 of 9	1		ENSP00000420297.2	O75469-4H0Y8E2
NR1I2	ENST00000493757.1 link	n.1240G>A		non_coding_transcript_exon_variant	Exon 5 of 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

GnomAD2 exomes

AF:

0.00106

AC:

265

AN:

249384

AF XY:

0.000764

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 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

African (AFR)

AF:

0.0162

AC:

541

AN:

33470

American (AMR)

AF:

0.000493

AC:

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000465

AC:

AN:

86052

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000809

AC:

AN:

1111852

Other (OTH)

AF:

0.000795

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

117

156

195

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00435

AC:

662

AN:

152326

Hom.:

Cov.:

AF XY:

0.00395

AC XY:

294

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.0154

AC:

639

AN:

41564

American (AMR)

AF:

0.000980

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68024

Other (OTH)

AF:

0.00236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

105

140

175

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00172

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

(source)

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

PhyloP100

3.1

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

Mutation Taster

=82/18

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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