3-119815779-G-C

Variant names:

• chr3-119815779-G-C
• rs35761343
• NM_003889.4:c.1108G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003889.4(NR1I2):​c.1108G>C​(p.Ala370Pro) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NR1I2 NM_003889.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.10
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1I2	NM_003889.4	c.1108G>C	p.Ala370Pro	missense_variant	Exon 8 of 9	ENST00000393716.8	NP_003880.3
NR1I2	NM_022002.3	c.1225G>C	p.Ala409Pro	missense_variant	Exon 8 of 9		NP_071285.1
NR1I2	NM_033013.3	c.997G>C	p.Ala333Pro	missense_variant	Exon 8 of 9		NP_148934.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR1I2	ENST00000393716.8	c.1108G>C	p.Ala370Pro	missense_variant	Exon 8 of 9	1	NM_003889.4	ENSP00000377319.3
NR1I2	ENST00000337940.4	c.1225G>C	p.Ala409Pro	missense_variant	Exon 8 of 9	1		ENSP00000336528.4
NR1I2	ENST00000466380.6	c.997G>C	p.Ala333Pro	missense_variant	Exon 8 of 9	1		ENSP00000420297.2
NR1I2	ENST00000493757.1	n.1240G>C		non_coding_transcript_exon_variant	Exon 5 of 6	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	.;.;.;.;D
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.026
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.93	D;D;D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Uncertain	2.6	.;.;.;.;M
PhyloP100		3.1
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.8	D;D;D;.;.
REVEL	Pathogenic	0.65
Sift	Uncertain	0.013	D;D;D;.;.
Sift4G	Uncertain	0.0070	D;D;D;.;.
Polyphen		1.0	.;.;.;.;D
Vest4		0.75
MutPred		0.74		Loss of ubiquitination at K374 (P = 0.2335);.;.;.;Loss of ubiquitination at K374 (P = 0.2335);
MVP		0.89
MPC		0.52
ClinPred		0.98	D
GERP RS		3.1
Varity_R		0.72
gMVP		0.84
Mutation Taster		=59/41	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: rs35761343; hg19: chr3-119534626;