3-119807329-C-T

Variant names:

• chr3-119807329-C-T
• rs12721613
• NM_003889.4:c.79C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003889.4(NR1I2):​c.79C>T​(p.Pro27Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00696 in 1,614,172 control chromosomes in the GnomAD database, including 615 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.036 (325 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (290 hom.)
• Consequence: NR1I2 NM_003889.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.42
• Publications: 23 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019551814).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1I2	NM_003889.4	c.79C>T	p.Pro27Ser	missense_variant	Exon 2 of 9	ENST00000393716.8	NP_003880.3
NR1I2	NM_022002.3	c.196C>T	p.Pro66Ser	missense_variant	Exon 2 of 9		NP_071285.1
NR1I2	NM_033013.3	c.79C>T	p.Pro27Ser	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.79C>T	p.Pro27Ser	missense_variant	Exon 2 of 9	1	NM_003889.4	ENSP00000377319.3
ENSG00000285585	ENST00000648112.1	c.*102C>T		3_prime_UTR_variant	Exon 18 of 18			ENSP00000497876.1

Frequencies

GnomAD3 genomes AF: 0.0357 AC: 5425 AN: 152170 Hom.: 326 Cov.: 32

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0130

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000661

Gnomad OTH AF: 0.0297

GnomAD2 exomes AF: 0.00980 AC: 2465 AN: 251492 AF XY: 0.00715

Gnomad AFR exome AF: 0.128

Gnomad AMR exome AF: 0.00662

Gnomad ASJ exome AF: 0.00367

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000747

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00397 AC: 5799 AN: 1461884 Hom.: 290 Cov.: 32 AF XY: 0.00347 AC XY: 2526 AN XY: 727242

African (AFR) AF: 0.126 AC: 4202 AN: 33476

American (AMR) AF: 0.00774 AC: 346 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00478 AC: 125 AN: 26136

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

South Asian (SAS) AF: 0.000313 AC: 27 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00641 AC: 37 AN: 5768

European-Non Finnish (NFE) AF: 0.000491 AC: 546 AN: 1112006

Other (OTH) AF: 0.00854 AC: 516 AN: 60396

GnomAD4 genome AF: 0.0357 AC: 5430 AN: 152288 Hom.: 325 Cov.: 32 AF XY: 0.0334 AC XY: 2490 AN XY: 74474

African (AFR) AF: 0.123 AC: 5109 AN: 41530

American (AMR) AF: 0.0130 AC: 199 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000661 AC: 45 AN: 68032

Other (OTH) AF: 0.0294 AC: 62 AN: 2110

Alfa AF: 0.0126 Hom.: 446

Bravo AF: 0.0410

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.127 AC: 559

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.0123 AC: 1490

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.000889

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.30
DANN	Benign	0.74
DEOGEN2	Benign	0.066	.;.;.;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.43	T;T;T;T;T
MetaRNN	Benign	0.0020	T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.6	.;.;.;L;L
PhyloP100		-1.4
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.34	N;N;N;.;.
REVEL	Benign	0.10
Sift	Benign	0.19	T;T;T;.;.
Sift4G	Benign	0.96	T;T;T;.;.
Vest4		0.030
MPC		0.084
ClinPred		0.00089	T
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.020
gMVP		0.55
Mutation Taster		=95/5	polymorphism (auto)

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: rs12721613; hg19: chr3-119526176;