Genetic Variant NR1I3:c.238+1099G>A (chr1-161234748-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_005122.5(NR1I3):c.238+1099G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.504 in 152,012 control chromosomes in the GnomAD database, including 20,167 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 0.50 ( 20167 hom., cov: 32)

Consequence

NR1I3
NM_005122.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.276

Publications

16 publications found

Variant links:

Genes affected

NR1I3 (HGNC:7969): (nuclear receptor subfamily 1 group I member 3) This gene encodes a member of the nuclear receptor superfamily, and is a key regulator of xenobiotic and endobiotic metabolism. The protein binds to DNA as a monomer or a heterodimer with the retinoid X receptor and regulates the transcription of target genes involved in drug metabolism and bilirubin clearance, such as cytochrome P450 family members. Unlike most nuclear receptors, this transcriptional regulator is constitutively active in the absence of ligand but is regulated by both agonists and inverse agonists. Ligand binding results in translocation of this protein to the nucleus, where it activates or represses target gene transcription. These ligands include bilirubin, a variety of foreign compounds, steroid hormones, and prescription drugs. In addition to drug metabolism, the CAR protein is also reported to regulate genes involved in glucose metabolism, lipid metabolism, cell proliferation, and circadian clock regulation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2020]

NR1I3 Gene-Disease associations (from GenCC):

intellectual disability
Inheritance: AD Classification: LIMITED Submitted by: G2P

NR1I3 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 (BayesDel_noAF=-0.92).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.65 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1I3	NM_005122.5 link	c.238+1099G>A		intron_variant	Intron 3 of 8	ENST00000367983.9	NP_005113.1	Q14994-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR1I3	ENST00000367983.9 link	c.238+1099G>A		intron_variant	Intron 3 of 8	1	NM_005122.5	ENSP00000356962.5		Q14994-2

Frequencies

GnomAD3 genomes

AF:

0.504

AC:

76493

AN:

151894

Hom.:

20120

Cov.:

show subpopulations

Gnomad AFR

AF:

0.657

Gnomad AMI

AF:

0.473

Gnomad AMR

AF:

0.483

Gnomad ASJ

AF:

0.376

Gnomad EAS

AF:

0.555

Gnomad SAS

AF:

0.475

Gnomad FIN

AF:

0.467

Gnomad MID

AF:

0.389

Gnomad NFE

AF:

0.427

Gnomad OTH

AF:

0.479

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

GnomAD4 genome

AF:

0.504

AC:

76601

AN:

152012

Hom.:

20167

Cov.:

AF XY:

0.505

AC XY:

37541

AN XY:

74278

show subpopulations

African (AFR)

AF:

0.657

AC:

27240

AN:

41462

American (AMR)

AF:

0.483

AC:

7391

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.376

AC:

1306

AN:

3470

East Asian (EAS)

AF:

0.555

AC:

2867

AN:

5166

South Asian (SAS)

AF:

0.475

AC:

2290

AN:

4824

European-Finnish (FIN)

AF:

0.467

AC:

4923

AN:

10540

Middle Eastern (MID)

AF:

0.412

AC:

121

AN:

294

European-Non Finnish (NFE)

AF:

0.427

AC:

29012

AN:

67948

Other (OTH)

AF:

0.484

AC:

1021

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1887

3774

5662

7549

9436

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

664

1328

1992

2656

3320

<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:

0.449

Hom.:

66146

Bravo

AF:

0.517

Asia WGS

AF:

0.533

AC:

1848

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

6.3

(source)

DANN

Benign

0.80

PhyloP100

-0.28

Mutation Taster

=100/0

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over