3-119807328-G-T

Variant names:

• chr3-119807328-G-T
• rs1183550879
• NM_003889.4:c.78G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003889.4(NR1I2):​c.78G>T​(p.Lys26Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,882 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: 0.0000041 (0 hom.)
• Consequence: NR1I2 NM_003889.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.434
• 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

ENSG00000285585 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.066951394).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1I2	NM_003889.4	c.78G>T	p.Lys26Asn	missense_variant	Exon 2 of 9	ENST00000393716.8	NP_003880.3
NR1I2	NM_022002.3	c.195G>T	p.Lys65Asn	missense_variant	Exon 2 of 9		NP_071285.1
NR1I2	NM_033013.3	c.78G>T	p.Lys26Asn	missense_variant	Exon 2 of 9		NP_148934.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR1I2	ENST00000393716.8	c.78G>T	p.Lys26Asn	missense_variant	Exon 2 of 9	1	NM_003889.4	ENSP00000377319.3
ENSG00000285585	ENST00000648112.1	c.*101G>T		3_prime_UTR_variant	Exon 18 of 18			ENSP00000497876.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000660 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

Jan 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.78G>T (p.K26N) alteration is located in exon 2 (coding exon 1) of the NR1I2 gene. This alteration results from a G to T substitution at nucleotide position 78, causing the lysine (K) at amino acid position 26 to be replaced by an asparagine (N). 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	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	1.0
DANN	Benign	0.89
DEOGEN2	Benign	0.065	.;.;.;.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.33	T;T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.067	T;T;T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.0	.;.;.;L;L
PhyloP100		-0.43
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.080	N;N;N;.;.
REVEL	Benign	0.11
Sift	Benign	0.36	T;T;T;.;.
Sift4G	Benign	0.50	T;T;T;.;.
Vest4		0.061
MutPred		0.34		.;.;Loss of ubiquitination at K65 (P = 0.0056);.;.;
MVP		0.30
MPC		0.097
ClinPred		0.21	T
GERP RS		-0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.055
gMVP		0.48
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs1183550879; hg19: chr3-119526175; COSMIC: COSV100561717; COSMIC: COSV100561717;