3-119811608-G-A

Variant names:

• chr3-119811608-G-A
• rs753350624
• NM_003889.4:c.401G>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.401G>A​(p.Gly134Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,726 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NR1I2 NM_003889.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.59

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 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=0.059516847).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1I2	NM_003889.4	c.401G>A	p.Gly134Glu	missense_variant	Exon 4 of 9	ENST00000393716.8	NP_003880.3
NR1I2	NM_022002.3	c.518G>A	p.Gly173Glu	missense_variant	Exon 4 of 9		NP_071285.1
NR1I2	NM_033013.3	c.401G>A	p.Gly134Glu	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.401G>A	p.Gly134Glu	missense_variant	Exon 4 of 9	1	NM_003889.4	ENSP00000377319.3
NR1I2	ENST00000337940.4	c.518G>A	p.Gly173Glu	missense_variant	Exon 4 of 9	1		ENSP00000336528.4
NR1I2	ENST00000466380.6	c.401G>A	p.Gly134Glu	missense_variant	Exon 4 of 9	1		ENSP00000420297.2
NR1I2	ENST00000493757.1	n.533G>A		non_coding_transcript_exon_variant	Exon 1 of 6	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250398 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135522

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461726 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727134

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.020
DANN	Benign	0.43
DEOGEN2	Benign	0.063	.;.;.;.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.54	T;T;T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.060	T;T;T;T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	-0.23	.;.;.;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.59	N;N;N;.;.
REVEL	Benign	0.17
Sift	Benign	1.0	T;T;T;.;.
Sift4G	Benign	1.0	T;T;T;.;.
Polyphen		0.0	.;.;.;.;B
Vest4		0.13
MutPred		0.29		Gain of glycosylation at S130 (P = 7e-04);Gain of glycosylation at S130 (P = 7e-04);.;Gain of glycosylation at S130 (P = 7e-04);Gain of glycosylation at S130 (P = 7e-04);
MVP		0.28
MPC		0.11
ClinPred		0.019	T
GERP RS		-4.6
Varity_R		0.053
gMVP		0.34

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

LitVar

Other links and lift over

dbSNP: rs753350624; hg19: chr3-119530455;