3-119807312-A-G

Variant names:

• chr3-119807312-A-G
• NM_003889.4:c.62A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003889.4(NR1I2):​c.62A>G​(p.Glu21Gly) 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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NR1I2 NM_003889.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.248
• Publications: 0 publications found

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

ENSG00000285585 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08883062).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1I2	NM_003889.4	c.62A>G	p.Glu21Gly	missense_variant	Exon 2 of 9	ENST00000393716.8	NP_003880.3
NR1I2	NM_022002.3	c.179A>G	p.Glu60Gly	missense_variant	Exon 2 of 9		NP_071285.1
NR1I2	NM_033013.3	c.62A>G	p.Glu21Gly	missense_variant	Exon 2 of 9		NP_148934.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR1I2	ENST00000393716.8	c.62A>G	p.Glu21Gly	missense_variant	Exon 2 of 9	1	NM_003889.4	ENSP00000377319.3
ENSG00000285585	ENST00000648112.1	c.*85A>G		3_prime_UTR_variant	Exon 18 of 18			ENSP00000497876.1

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

Jan 04, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.62A>G (p.E21G) alteration is located in exon 2 (coding exon 1) of the NR1I2 gene. This alteration results from a A to G substitution at nucleotide position 62, causing the glutamic acid (E) at amino acid position 21 to be replaced by a glycine (G). 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	0.061
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	10
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	.;.;.;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.34	T;T;T;T;T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.089	T;T;T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	0.69	.;.;.;N;N
PhyloP100		0.25
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.88	N;N;N;.;.
REVEL	Benign	0.23
Sift	Benign	0.063	T;T;D;.;.
Sift4G	Uncertain	0.054	T;D;T;.;.
Vest4		0.075
MutPred		0.22		.;.;Loss of stability (P = 0.0646);.;.;
MVP		0.38
MPC		0.096
ClinPred		0.13	T
GERP RS		2.6
Varity_R		0.053
gMVP		0.53
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

hg19: chr3-119526159;