3-119812794-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003889.4(NR1I2):c.628A>G(p.Lys210Glu) 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. 12/21 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: 2.58

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15203908).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR1I2	NM_003889.4	c.628A>G	p.Lys210Glu	missense_variant	5/9	ENST00000393716.8
NR1I2	NM_022002.3	c.745A>G	p.Lys249Glu	missense_variant	5/9
NR1I2	NM_033013.3	c.520-3A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR1I2	ENST00000393716.8	c.628A>G	p.Lys210Glu	missense_variant	5/9	1	NM_003889.4	P2
NR1I2	ENST00000337940.4	c.745A>G	p.Lys249Glu	missense_variant	5/9	1		A2
NR1I2	ENST00000466380.6	c.520-3A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		A2
NR1I2	ENST00000493757.1	n.760A>G		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

Jan 24, 2024

The c.628A>G (p.K210E) alteration is located in exon 5 (coding exon 4) of the NR1I2 gene. This alteration results from a A to G substitution at nucleotide position 628, causing the lysine (K) at amino acid position 210 to be replaced by a glutamic acid (E). 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	0.11
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
Cadd	Benign	20
Dann	Benign	0.77
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.74	T;T;T
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Uncertain	0.078	D
MutationTaster	Benign	0.74	D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.48	N;N;.
REVEL	Uncertain	0.38
Sift	Benign	0.86	T;T;.
Sift4G	Benign	0.99	T;T;.
Polyphen		0.16	.;.;B
Vest4		0.42
MutPred		0.43		Loss of MoRF binding (P = 0.0049);.;Loss of MoRF binding (P = 0.0049);
MVP		0.72
MPC		0.15
ClinPred		0.15	T
GERP RS		3.4
Varity_R		0.25
gMVP		0.38

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-119531641;