3-119812953-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_003889.4(NR1I2):c.787T>C(p.Tyr263His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,613,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y263C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: NR1I2 NM_003889.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.412

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17264718).
• BP6: Variant 3-119812953-T-C is Benign according to our data. Variant chr3-119812953-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2377653.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR1I2	NM_003889.4	c.787T>C	p.Tyr263His	missense_variant	5/9	ENST00000393716.8
NR1I2	NM_022002.3	c.904T>C	p.Tyr302His	missense_variant	5/9
NR1I2	NM_033013.3	c.676T>C	p.Tyr226His	missense_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR1I2	ENST00000393716.8	c.787T>C	p.Tyr263His	missense_variant	5/9	1	NM_003889.4	P2
NR1I2	ENST00000337940.4	c.904T>C	p.Tyr302His	missense_variant	5/9	1		A2
NR1I2	ENST00000466380.6	c.676T>C	p.Tyr226His	missense_variant	5/9	1		A2
NR1I2	ENST00000493757.1	n.919T>C		non_coding_transcript_exon_variant	2/6	2

Frequencies

GnomAD3 genomes AF: 0.0000525 AC: 8 AN: 152256 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000364 AC: 9 AN: 247174 Hom.: 0 AF XY: 0.0000299 AC XY: 4 AN XY: 133844

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000362

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000294 AC: 43 AN: 1461036 Hom.: 0 Cov.: 32 AF XY: 0.0000303 AC XY: 22 AN XY: 726802

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000403

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74392

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000384

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000907

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	14
Dann	Benign	0.89
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.083	T;T;T;T;T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.17	T;T;T;T;T
MetaSVM	Uncertain	-0.020	T
MutationTaster	Benign	0.79	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.63	N;N;N;.;.
REVEL	Uncertain	0.30
Sift	Benign	0.51	T;T;T;.;.
Sift4G	Benign	0.54	T;T;T;.;.
Polyphen		0.0010	.;.;.;.;B
Vest4		0.11
MutPred		0.55		Loss of stability (P = 0.0448);.;.;.;Loss of stability (P = 0.0448);
MVP		0.61
MPC		0.11
ClinPred		0.0074	T
GERP RS		-2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.18
gMVP		0.42

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: rs761179278; hg19: chr3-119531800;