3-119812708-G-A

Position:

• chr3-119812708-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003889.4(NR1I2):​c.542G>A​(p.Gly181Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 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: not found (cov: 32)
• Consequence: NR1I2 NM_003889.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.317

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.052084327).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR1I2	NM_003889.4	c.542G>A	p.Gly181Asp	missense_variant	5/9	ENST00000393716.8	NP_003880.3
NR1I2	NM_022002.3	c.659G>A	p.Gly220Asp	missense_variant	5/9		NP_071285.1
NR1I2	NM_033013.3	c.520-89G>A		intron_variant			NP_148934.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR1I2	ENST00000393716.8	c.542G>A	p.Gly181Asp	missense_variant	5/9	1	NM_003889.4	ENSP00000377319.3
NR1I2	ENST00000337940.4	c.659G>A	p.Gly220Asp	missense_variant	5/9	1		ENSP00000336528.4
NR1I2	ENST00000466380.6	c.520-89G>A		intron_variant		1		ENSP00000420297.2
NR1I2	ENST00000493757.1	n.674G>A		non_coding_transcript_exon_variant	2/6	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 19, 2024

The c.542G>A (p.G181D) alteration is located in exon 5 (coding exon 4) of the NR1I2 gene. This alteration results from a G to A substitution at nucleotide position 542, causing the glycine (G) at amino acid position 181 to be replaced by an aspartic acid (D). 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	Benign	0.076
BayesDel_addAF	Benign	-0.0012	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	11
DANN	Benign	0.80
DEOGEN2	Benign	0.062	.;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.56	T;T;T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.052	T;T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	0.69	.;.;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.11	N;N;.
REVEL	Benign	0.17
Sift	Benign	0.29	T;T;.
Sift4G	Benign	0.45	T;T;.
Polyphen		0.0010	.;.;B
Vest4		0.21
MutPred		0.32		Gain of glycosylation at S179 (P = 0.0704);.;Gain of glycosylation at S179 (P = 0.0704);
MVP		0.38
MPC		0.11
ClinPred		0.060	T
GERP RS		-1.5
Varity_R		0.044
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-119531555; COSMIC: COSV61978105; COSMIC: COSV61978105;