3-119810095-C-T

Variant names:

• chr3-119810095-C-T
• NM_003889.4:c.232C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003889.4(NR1I2):​c.232C>T​(p.Pro78Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 3.83
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1I2	NM_003889.4	c.232C>T	p.Pro78Ser	missense_variant	Exon 3 of 9	ENST00000393716.8	NP_003880.3
NR1I2	NM_022002.3	c.349C>T	p.Pro117Ser	missense_variant	Exon 3 of 9		NP_071285.1
NR1I2	NM_033013.3	c.232C>T	p.Pro78Ser	missense_variant	Exon 3 of 9		NP_148934.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR1I2	ENST00000393716.8	c.232C>T	p.Pro78Ser	missense_variant	Exon 3 of 9	1	NM_003889.4	ENSP00000377319.3
NR1I2	ENST00000337940.4	c.349C>T	p.Pro117Ser	missense_variant	Exon 3 of 9	1		ENSP00000336528.4
NR1I2	ENST00000466380.6	c.232C>T	p.Pro78Ser	missense_variant	Exon 3 of 9	1		ENSP00000420297.2
NR1I2	ENST00000474090.1	n.520C>T		non_coding_transcript_exon_variant	Exon 3 of 3	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 31, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.232C>T (p.P78S) alteration is located in exon 3 (coding exon 2) of the NR1I2 gene. This alteration results from a C to T substitution at nucleotide position 232, causing the proline (P) at amino acid position 78 to be replaced by a serine (S). 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	0.17
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	.;.;.;.;D
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.66	T;T;T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.71	D;D;D;D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Benign	1.1	.;.;.;L;L
PhyloP100		3.8
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-6.6	D;D;D;.;.
REVEL	Uncertain	0.55
Sift	Uncertain	0.0040	D;D;D;.;.
Sift4G	Uncertain	0.0060	D;D;D;.;.
Vest4		0.27
MutPred		0.50		.;.;Loss of catalytic residue at P117 (P = 0.0419);.;.;
MVP		0.91
MPC		0.21
ClinPred		0.98	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.68
Mutation Taster		=65/35	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

hg19: chr3-119528942;