3-119811608-G-C

Variant names:

• chr3-119811608-G-C
• rs753350624
• NM_003889.4:c.401G>C

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.401G>C​(p.Gly134Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NR1I2 NM_003889.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.59
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08121756).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1I2	NM_003889.4	c.401G>C	p.Gly134Ala	missense_variant	Exon 4 of 9	ENST00000393716.8	NP_003880.3
NR1I2	NM_022002.3	c.518G>C	p.Gly173Ala	missense_variant	Exon 4 of 9		NP_071285.1
NR1I2	NM_033013.3	c.401G>C	p.Gly134Ala	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>C	p.Gly134Ala	missense_variant	Exon 4 of 9	1	NM_003889.4	ENSP00000377319.3
NR1I2	ENST00000337940.4	c.518G>C	p.Gly173Ala	missense_variant	Exon 4 of 9	1		ENSP00000336528.4
NR1I2	ENST00000466380.6	c.401G>C	p.Gly134Ala	missense_variant	Exon 4 of 9	1		ENSP00000420297.2
NR1I2	ENST00000493757.1	n.533G>C		non_coding_transcript_exon_variant	Exon 1 of 6	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461726 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727134

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111944

Other (OTH) AF: 0.00 AC: 0 AN: 60390

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 15, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.401G>C (p.G134A) alteration is located in exon 4 (coding exon 3) of the NR1I2 gene. This alteration results from a G to C substitution at nucleotide position 401, causing the glycine (G) at amino acid position 134 to be replaced by an alanine (A). 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	0.077
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.023
DANN	Benign	0.19
DEOGEN2	Benign	0.062	.;.;.;.;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.56	T;T;T;T;T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.081	T;T;T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	0.58	.;.;.;N;N
PhyloP100		-1.6
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.48	N;N;N;.;.
REVEL	Benign	0.15
Sift	Benign	0.76	T;T;T;.;.
Sift4G	Benign	0.83	T;T;T;.;.
Polyphen		0.0020	.;.;.;.;B
Vest4		0.16
MutPred		0.20		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		0.089
ClinPred		0.033	T
GERP RS		-4.6
Varity_R		0.031
gMVP		0.32
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

dbSNP: rs753350624; hg19: chr3-119530455;