NM_003889.4:c.317G>A

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_003889.4(NR1I2):c.317G>A(p.Gly106Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G106V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

NR1I2
NM_003889.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.51

Publications

2 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: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.956

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1I2	NM_003889.4 link	c.317G>A	p.Gly106Asp	missense_variant	Exon 3 of 9	ENST00000393716.8	NP_003880.3	O75469-1
NR1I2	NM_022002.3 link	c.434G>A	p.Gly145Asp	missense_variant	Exon 3 of 9		NP_071285.1	O75469-7F1D8P9
NR1I2	NM_033013.3 link	c.317G>A	p.Gly106Asp	missense_variant	Exon 3 of 9		NP_148934.1	O75469-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NR1I2	ENST00000393716.8 link	c.317G>A	p.Gly106Asp	missense_variant	Exon 3 of 9	1	NM_003889.4	ENSP00000377319.3	O75469-1J3KPQ3
NR1I2	ENST00000337940.4 link	c.434G>A	p.Gly145Asp	missense_variant	Exon 3 of 9	1		ENSP00000336528.4	O75469-7
NR1I2	ENST00000466380.6 link	c.317G>A	p.Gly106Asp	missense_variant	Exon 3 of 9	1		ENSP00000420297.2	O75469-4H0Y8E2
NR1I2	ENST00000474090.1 link	n.605G>A		non_coding_transcript_exon_variant	Exon 3 of 3	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000432

AC:

AN:

231552

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000177

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1456008

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724054

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33352

American (AMR)

AF:

0.00

AC:

AN:

43940

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25988

East Asian (EAS)

AF:

0.00

AC:

AN:

39434

South Asian (SAS)

AF:

0.00

AC:

AN:

85614

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52210

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109650

Other (OTH)

AF:

0.0000167

AC:

AN:

60058

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.59

BayesDel_noAF

Pathogenic

0.61

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

.;.;.;.;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.99

D;D;D;D;D

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.96

D;D;D;D;D

MetaSVM

Pathogenic

0.96

MutationAssessor

Pathogenic

4.5

.;.;.;H;H

PhyloP100

9.5

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-6.3

D;D;D;.;.

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;D;D;.;.

Sift4G

Pathogenic

0.0

D;D;D;.;.

Vest4

0.92

MutPred

0.81

.;.;Loss of glycosylation at K147 (P = 0.0285);.;.;

MVP

0.95

MPC

0.52

ClinPred

1.0

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.51

gMVP

0.86

Mutation Taster

=9/91

disease causing

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over