3-119811644-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003889.4(NR1I2):c.437A>G(p.Glu146Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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: 6.38

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.764

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR1I2	NM_003889.4	c.437A>G	p.Glu146Gly	missense_variant	4/9	ENST00000393716.8
NR1I2	NM_022002.3	c.554A>G	p.Glu185Gly	missense_variant	4/9
NR1I2	NM_033013.3	c.437A>G	p.Glu146Gly	missense_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR1I2	ENST00000393716.8	c.437A>G	p.Glu146Gly	missense_variant	4/9	1	NM_003889.4	P2
NR1I2	ENST00000337940.4	c.554A>G	p.Glu185Gly	missense_variant	4/9	1		A2
NR1I2	ENST00000466380.6	c.437A>G	p.Glu146Gly	missense_variant	4/9	1		A2
NR1I2	ENST00000493757.1	n.569A>G		non_coding_transcript_exon_variant	1/6	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Jun 24, 2022

The c.437A>G (p.E146G) alteration is located in exon 4 (coding exon 3) of the NR1I2 gene. This alteration results from a A to G substitution at nucleotide position 437, causing the glutamic acid (E) at amino acid position 146 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	0.099
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
Cadd	Uncertain	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T;T;T;T;T
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-5.8	D;D;D;.;.
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	D;D;D;.;.
Sift4G	Uncertain	0.029	D;D;D;.;.
Polyphen		0.96	.;.;.;.;D
Vest4		0.57
MutPred		0.40		Gain of MoRF binding (P = 0.0503);Gain of MoRF binding (P = 0.0503);.;Gain of MoRF binding (P = 0.0503);Gain of MoRF binding (P = 0.0503);
MVP		0.91
MPC		0.12
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.45
gMVP		0.45

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-119530491;