rs12721613

Positions:

• chr3-119807329-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000393716.8(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. 15/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.036 (325 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (290 hom.)
• Consequence: NR1I2 ENST00000393716.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.42

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
NR1I2	NM_003889.4	c.79C>T	p.Pro27Ser	missense_variant	2/9	ENST00000393716.8	NP_003880.3
NR1I2	NM_022002.3	c.196C>T	p.Pro66Ser	missense_variant	2/9		NP_071285.1
NR1I2	NM_033013.3	c.79C>T	p.Pro27Ser	missense_variant	2/9		NP_148934.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR1I2	ENST00000393716.8	c.79C>T	p.Pro27Ser	missense_variant	2/9	1	NM_003889.4	ENSP00000377319	P2
NR1I2	ENST00000337940.4	c.196C>T	p.Pro66Ser	missense_variant	2/9	1		ENSP00000336528	A2
NR1I2	ENST00000466380.6	c.79C>T	p.Pro27Ser	missense_variant	2/9	1		ENSP00000420297	A2
NR1I2	ENST00000474090.1	n.367C>T		non_coding_transcript_exon_variant	2/3	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

GnomAD3 exomes AF: 0.00980 AC: 2465 AN: 251492 Hom.: 128 AF XY: 0.00715 AC XY: 972 AN XY: 135922

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 SAS exome AF: 0.000163

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

Gnomad4 AFR exome AF: 0.126

Gnomad4 AMR exome AF: 0.00774

Gnomad4 ASJ exome AF: 0.00478

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000313

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000491

Gnomad4 OTH exome AF: 0.00854

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

Gnomad4 AFR AF: 0.123

Gnomad4 AMR AF: 0.0130

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000661

Gnomad4 OTH AF: 0.0294

Alfa AF: 0.00775 Hom.: 120

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
MutationTaster	Benign	1.0	N
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs12721613; hg19: chr3-119526176;