3-119807328-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003889.4(NR1I2):c.78G>T(p.Lys26Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: NR1I2 NM_003889.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.434

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=0.066951394).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR1I2	NM_003889.4	c.78G>T	p.Lys26Asn	missense_variant	2/9	ENST00000393716.8
NR1I2	NM_022002.3	c.195G>T	p.Lys65Asn	missense_variant	2/9
NR1I2	NM_033013.3	c.78G>T	p.Lys26Asn	missense_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR1I2	ENST00000393716.8	c.78G>T	p.Lys26Asn	missense_variant	2/9	1	NM_003889.4	P2
NR1I2	ENST00000337940.4	c.195G>T	p.Lys65Asn	missense_variant	2/9	1		A2
NR1I2	ENST00000466380.6	c.78G>T	p.Lys26Asn	missense_variant	2/9	1		A2
NR1I2	ENST00000474090.1	n.366G>T		non_coding_transcript_exon_variant	2/3	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000660 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2024

The c.78G>T (p.K26N) alteration is located in exon 2 (coding exon 1) of the NR1I2 gene. This alteration results from a G to T substitution at nucleotide position 78, causing the lysine (K) at amino acid position 26 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	1.0
Dann	Benign	0.89
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.33	T;T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.067	T;T;T;T;T
MetaSVM	Benign	-0.49	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.080	N;N;N;.;.
REVEL	Benign	0.11
Sift	Benign	0.36	T;T;T;.;.
Sift4G	Benign	0.50	T;T;T;.;.
Vest4		0.061
MutPred		0.34		.;.;Loss of ubiquitination at K65 (P = 0.0056);.;.;
MVP		0.30
MPC		0.097
ClinPred		0.21	T
GERP RS		-0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.055
gMVP		0.48

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: rs1183550879; hg19: chr3-119526175; COSMIC: COSV100561717; COSMIC: COSV100561717;