Genetic Variant NR1I2:c.-23+8234A>G (chr3-119790534-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003889.4(NR1I2):c.-23+8234A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.351 in 152,048 control chromosomes in the GnomAD database, including 9,819 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.35 ( 9819 hom., cov: 32)

Consequence

NR1I2
NM_003889.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.653

Publications

11 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.02).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.415 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
NR1I2	NM_003889.4 link	c.-23+8234A>G	intron_variant	Intron 1 of 8	ENST00000393716.8	NP_003880.3	O75469-1
NR1I2	NM_022002.3 link	c.95+7682A>G	intron_variant	Intron 1 of 8		NP_071285.1	O75469-7F1D8P9
NR1I2	NM_033013.3 link	c.-23+8234A>G	intron_variant	Intron 1 of 8		NP_148934.1	O75469-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR1I2	ENST00000393716.8 link	c.-23+8234A>G		intron_variant	Intron 1 of 8	1	NM_003889.4	ENSP00000377319.3		O75469-1J3KPQ3
ENSG00000285585	ENST00000648112.1 link	c.*2-16695A>G		intron_variant	Intron 17 of 17			ENSP00000497876.1

Frequencies

GnomAD3 genomes

AF:

0.350

AC:

53235

AN:

151930

Hom.:

9802

Cov.:

show subpopulations

Gnomad AFR

AF:

0.419

Gnomad AMI

AF:

0.251

Gnomad AMR

AF:

0.405

Gnomad ASJ

AF:

0.228

Gnomad EAS

AF:

0.379

Gnomad SAS

AF:

0.364

Gnomad FIN

AF:

0.257

Gnomad MID

AF:

0.316

Gnomad NFE

AF:

0.315

Gnomad OTH

AF:

0.351

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.351

AC:

53301

AN:

152048

Hom.:

9819

Cov.:

AF XY:

0.347

AC XY:

25806

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.420

AC:

17405

AN:

41454

American (AMR)

AF:

0.405

AC:

6180

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.228

AC:

790

AN:

3472

East Asian (EAS)

AF:

0.380

AC:

1966

AN:

5172

South Asian (SAS)

AF:

0.364

AC:

1755

AN:

4822

European-Finnish (FIN)

AF:

0.257

AC:

2715

AN:

10574

Middle Eastern (MID)

AF:

0.310

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.315

AC:

21432

AN:

67966

Other (OTH)

AF:

0.349

AC:

739

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1753

3506

5259

7012

8765

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

520

1040

1560

2080

2600

<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:

0.326

Hom.:

16902

Bravo

AF:

0.367

Asia WGS

AF:

0.389

AC:

1351

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.35

(source)

DANN

Benign

0.40

PhyloP100

-0.65

Mutation Taster

=100/0

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over