rs35761343

chr3-119815779-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_003889.4(NR1I2):c.1108G>A(p.Ala370Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000802 in 1,613,732 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 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 0.0043 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (7 hom.)
• Consequence: NR1I2 NM_003889.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.10

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=0.00626415).
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000432 (632/1461406) while in subpopulation AFR AF= 0.0162 (541/33470). AF 95% confidence interval is 0.015. There are 7 homozygotes in gnomad4_exome. There are 284 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR1I2	NM_003889.4	c.1108G>A	p.Ala370Thr	missense_variant	8/9	ENST00000393716.8
NR1I2	NM_022002.3	c.1225G>A	p.Ala409Thr	missense_variant	8/9
NR1I2	NM_033013.3	c.997G>A	p.Ala333Thr	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR1I2	ENST00000393716.8	c.1108G>A	p.Ala370Thr	missense_variant	8/9	1	NM_003889.4	P2
NR1I2	ENST00000337940.4	c.1225G>A	p.Ala409Thr	missense_variant	8/9	1		A2
NR1I2	ENST00000466380.6	c.997G>A	p.Ala333Thr	missense_variant	8/9	1		A2
NR1I2	ENST00000493757.1	n.1240G>A		non_coding_transcript_exon_variant	5/6	2

Frequencies

GnomAD3 genomes AF: 0.00435 AC: 662 AN: 152208 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00106 AC: 265 AN: 249384 Hom.: 3 AF XY: 0.000764 AC XY: 103 AN XY: 134846

Gnomad AFR exome AF: 0.0153

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0000659

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000432 AC: 632 AN: 1461406 Hom.: 7 Cov.: 32 AF XY: 0.000391 AC XY: 284 AN XY: 726920

Gnomad4 AFR exome AF: 0.0162

Gnomad4 AMR exome AF: 0.000493

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000465

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.000795

GnomAD4 genome AF: 0.00435 AC: 662 AN: 152326 Hom.: 4 Cov.: 32 AF XY: 0.00395 AC XY: 294 AN XY: 74488

Gnomad4 AFR AF: 0.0154

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.000942 Hom.: 0

Bravo AF: 0.00532

ESP6500AA AF: 0.0150 AC: 66

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00145 AC: 176

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.85	T;T;D;T;T
MetaRNN	Benign	0.0063	T;T;T;T;T
MetaSVM	Uncertain	0.10	D
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.5	N;N;N;.;.
REVEL	Uncertain	0.31
Sift	Benign	0.057	T;D;D;.;.
Sift4G	Benign	0.098	T;T;T;.;.
Polyphen		0.99	.;.;.;.;D
Vest4		0.24
MVP		0.88
MPC		0.23
ClinPred		0.045	T
GERP RS		3.1
Varity_R		0.32
gMVP		0.45

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

Publications

LitVar

Other links and lift over

dbSNP: rs35761343; hg19: chr3-119534626;