3-119810183-T-A

Position:

chr3-119810183-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_003889.4(NR1I2):c.320T>A(p.Met107Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000224 in 1,608,222 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.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

NR1I2
NM_003889.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.91

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:

NR1I2 (HGNC:):

NR1I2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.916

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR1I2	NM_003889.4 linkuse as main transcript	c.320T>A	p.Met107Lys	missense_variant	3/9	ENST00000393716.8	NP_003880.3	O75469-1
NR1I2	NM_022002.3 linkuse as main transcript	c.437T>A	p.Met146Lys	missense_variant	3/9		NP_071285.1	O75469-7F1D8P9
NR1I2	NM_033013.3 linkuse as main transcript	c.320T>A	p.Met107Lys	missense_variant	3/9		NP_148934.1	O75469-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NR1I2	ENST00000393716.8 linkuse as main transcript	c.320T>A	p.Met107Lys	missense_variant	3/9	1	NM_003889.4	ENSP00000377319.3	O75469-1J3KPQ3
NR1I2	ENST00000337940.4 linkuse as main transcript	c.437T>A	p.Met146Lys	missense_variant	3/9	1		ENSP00000336528.4	O75469-7
NR1I2	ENST00000466380.6 linkuse as main transcript	c.320T>A	p.Met107Lys	missense_variant	3/9	1		ENSP00000420297.2	O75469-4H0Y8E2
NR1I2	ENST00000474090.1 linkuse as main transcript	n.608T>A		non_coding_transcript_exon_variant	3/3	1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000433

AC:

AN:

231120

Hom.:

AF XY:

0.00

AC XY:

AN XY:

126906

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000976

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000240

AC:

AN:

1456162

Hom.:

Cov.:

AF XY:

0.0000249

AC XY:

AN XY:

724152

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000306

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152060

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74260

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2024

The c.320T>A (p.M107K) alteration is located in exon 3 (coding exon 2) of the NR1I2 gene. This alteration results from a T to A substitution at nucleotide position 320, causing the methionine (M) at amino acid position 107 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.79

.;.;.;.;D

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.76

LIST_S2

Pathogenic

0.98

D;D;D;D;D

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.92

D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.2

.;.;.;H;H

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-5.4

D;D;D;.;.

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

D;D;D;.;.

Sift4G

Pathogenic

0.0

D;D;D;.;.

Vest4

0.85

MutPred

0.75

.;.;Loss of stability (P = 0.0172);.;.;

MVP

0.95

MPC

0.56

ClinPred

1.0

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.88

gMVP

0.97

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over