3-119810178-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_003889.4(NR1I2):c.315C>T(p.Ser105=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,609,474 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0081 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00094 (15 hom.)
• Consequence: NR1I2 NM_003889.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.02

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 3-119810178-C-T is Benign according to our data. Variant chr3-119810178-C-T is described in ClinVar as [Benign]. Clinvar id is 773133.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.02 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00806 (1228/152354) while in subpopulation AFR AF= 0.0283 (1178/41586). AF 95% confidence interval is 0.027. There are 14 homozygotes in gnomad4. There are 560 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR1I2	NM_003889.4	c.315C>T	p.Ser105=	synonymous_variant	3/9	ENST00000393716.8
NR1I2	NM_022002.3	c.432C>T	p.Ser144=	synonymous_variant	3/9
NR1I2	NM_033013.3	c.315C>T	p.Ser105=	synonymous_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR1I2	ENST00000393716.8	c.315C>T	p.Ser105=	synonymous_variant	3/9	1	NM_003889.4	P2
NR1I2	ENST00000337940.4	c.432C>T	p.Ser144=	synonymous_variant	3/9	1		A2
NR1I2	ENST00000466380.6	c.315C>T	p.Ser105=	synonymous_variant	3/9	1		A2
NR1I2	ENST00000474090.1	n.603C>T		non_coding_transcript_exon_variant	3/3	1

Frequencies

GnomAD3 genomes AF: 0.00805 AC: 1225 AN: 152236 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0283

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00216 AC: 505 AN: 234112 Hom.: 4 AF XY: 0.00173 AC XY: 223 AN XY: 128530

Gnomad AFR exome AF: 0.0307

Gnomad AMR exome AF: 0.00174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000101

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000144

Gnomad OTH exome AF: 0.000700

GnomAD4 exome AF: 0.000942 AC: 1372 AN: 1457120 Hom.: 15 Cov.: 33 AF XY: 0.000806 AC XY: 584 AN XY: 724696

Gnomad4 AFR exome AF: 0.0302

Gnomad4 AMR exome AF: 0.00191

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000466

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000108

Gnomad4 OTH exome AF: 0.00248

GnomAD4 genome AF: 0.00806 AC: 1228 AN: 152354 Hom.: 14 Cov.: 32 AF XY: 0.00752 AC XY: 560 AN XY: 74490

Gnomad4 AFR AF: 0.0283

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00107 Hom.: 0

Bravo AF: 0.00976

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 29, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
Cadd	Benign	9.7
Dann	Benign	0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs150651210; hg19: chr3-119529025;