3-119811553-G-C

Variant names:

• chr3-119811553-G-C
• rs755621657
• NM_003889.4:c.346G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003889.4(NR1I2):​c.346G>C​(p.Glu116Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign 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. E116K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NR1I2 NM_003889.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.92
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27528948).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1I2	NM_003889.4	c.346G>C	p.Glu116Gln	missense_variant	Exon 4 of 9	ENST00000393716.8	NP_003880.3
NR1I2	NM_022002.3	c.463G>C	p.Glu155Gln	missense_variant	Exon 4 of 9		NP_071285.1
NR1I2	NM_033013.3	c.346G>C	p.Glu116Gln	missense_variant	Exon 4 of 9		NP_148934.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR1I2	ENST00000393716.8	c.346G>C	p.Glu116Gln	missense_variant	Exon 4 of 9	1	NM_003889.4	ENSP00000377319.3
NR1I2	ENST00000337940.4	c.463G>C	p.Glu155Gln	missense_variant	Exon 4 of 9	1		ENSP00000336528.4
NR1I2	ENST00000466380.6	c.346G>C	p.Glu116Gln	missense_variant	Exon 4 of 9	1		ENSP00000420297.2
NR1I2	ENST00000493757.1	n.478G>C		non_coding_transcript_exon_variant	Exon 1 of 6	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	0.0049	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.27	.;.;.;.;T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.28	T;T;T;T;T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.28	T;T;T;T;T
MetaSVM	Uncertain	0.52	D
MutationAssessor	Benign	1.9	.;.;.;L;L
PhyloP100		3.9
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.8	N;N;N;.;.
REVEL	Uncertain	0.32
Sift	Benign	0.061	T;D;D;.;.
Sift4G	Benign	0.092	T;D;T;.;.
Polyphen		0.46	.;.;.;.;P
Vest4		0.29
MutPred		0.36		Gain of glycosylation at S114 (P = 0.006);Gain of glycosylation at S114 (P = 0.006);.;Gain of glycosylation at S114 (P = 0.006);Gain of glycosylation at S114 (P = 0.006);
MVP		0.75
MPC		0.088
ClinPred		0.37	T
GERP RS		4.0
Varity_R		0.050
gMVP		0.48
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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

dbSNP: rs755621657; hg19: chr3-119530400;