rs573567813

Variant names:

• chr3-119811628-C-A
• rs573567813
• NM_003889.4:c.421C>A

Your query was ambiguous. Multiple possible variants found:

• chr3-119811628-C-A
• chr3-119811628-C-G

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.421C>A​(p.Gln141Lys) 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 1,461,698 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q141E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NR1I2 NM_003889.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.27
• 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=0.07641077).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1I2	NM_003889.4	c.421C>A	p.Gln141Lys	missense_variant	Exon 4 of 9	ENST00000393716.8	NP_003880.3
NR1I2	NM_022002.3	c.538C>A	p.Gln180Lys	missense_variant	Exon 4 of 9		NP_071285.1
NR1I2	NM_033013.3	c.421C>A	p.Gln141Lys	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.421C>A	p.Gln141Lys	missense_variant	Exon 4 of 9	1	NM_003889.4	ENSP00000377319.3
NR1I2	ENST00000337940.4	c.538C>A	p.Gln180Lys	missense_variant	Exon 4 of 9	1		ENSP00000336528.4
NR1I2	ENST00000466380.6	c.421C>A	p.Gln141Lys	missense_variant	Exon 4 of 9	1		ENSP00000420297.2
NR1I2	ENST00000493757.1	n.553C>A		non_coding_transcript_exon_variant	Exon 1 of 6	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461698 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727142

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

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111958

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	4.3
DANN	Benign	0.21
DEOGEN2	Benign	0.061	.;.;.;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.64	T;T;T;T;T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.076	T;T;T;T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	-0.30	.;.;.;N;N
PhyloP100		1.3
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.17	N;N;N;.;.
REVEL	Benign	0.23
Sift	Benign	1.0	T;T;T;.;.
Sift4G	Benign	1.0	T;T;T;.;.
Polyphen		0.0	.;.;.;.;B
Vest4		0.15
MutPred		0.43		Gain of ubiquitination at Q141 (P = 9e-04);Gain of ubiquitination at Q141 (P = 9e-04);.;Gain of ubiquitination at Q141 (P = 9e-04);Gain of ubiquitination at Q141 (P = 9e-04);
MVP		0.49
MPC		0.10
ClinPred		0.016	T
GERP RS		3.9
Varity_R		0.19
gMVP		0.41
Mutation Taster		=84/16	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: rs573567813; hg19: chr3-119530475; COSMIC: COSV61977567; COSMIC: COSV61977567;