NM_003889.4:c.248C>A

Variant names:

• chr3-119810111-C-A
• NM_003889.4:c.248C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003889.4(NR1I2):​c.248C>A​(p.Ala83Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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: 0.0000048 (0 hom.)
• Consequence: NR1I2 NM_003889.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.573
• Publications: 0 publications found

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]

NR1I2 Gene-Disease associations (from GenCC):

• pediatric lymphoma

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17491868).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1I2	NM_003889.4	c.248C>A	p.Ala83Asp	missense_variant	Exon 3 of 9	ENST00000393716.8	NP_003880.3
NR1I2	NM_022002.3	c.365C>A	p.Ala122Asp	missense_variant	Exon 3 of 9		NP_071285.1
NR1I2	NM_033013.3	c.248C>A	p.Ala83Asp	missense_variant	Exon 3 of 9		NP_148934.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR1I2	ENST00000393716.8	c.248C>A	p.Ala83Asp	missense_variant	Exon 3 of 9	1	NM_003889.4	ENSP00000377319.3
NR1I2	ENST00000337940.4	c.365C>A	p.Ala122Asp	missense_variant	Exon 3 of 9	1		ENSP00000336528.4
NR1I2	ENST00000466380.6	c.248C>A	p.Ala83Asp	missense_variant	Exon 3 of 9	1		ENSP00000420297.2
NR1I2	ENST00000474090.1	n.536C>A		non_coding_transcript_exon_variant	Exon 3 of 3	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461412 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727054

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53122

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111908

Other (OTH) AF: 0.00 AC: 0 AN: 60358

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 30, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.248C>A (p.A83D) alteration is located in exon 3 (coding exon 2) of the NR1I2 gene. This alteration results from a C to A substitution at nucleotide position 248, causing the alanine (A) at amino acid position 83 to be replaced by an aspartic acid (D). 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	0.15
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	.;.;.;.;D
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.23	T;T;T;T;T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.17	T;T;T;T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	-0.30	.;.;.;N;N
PhyloP100		-0.57
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.80	N;N;N;.;.
REVEL	Benign	0.23
Sift	Benign	0.73	T;T;T;.;.
Sift4G	Benign	0.47	T;T;T;.;.
Vest4		0.20
MutPred		0.35		.;.;Gain of glycosylation at T126 (P = 0.0157);.;.;
MVP		0.67
MPC		0.27
ClinPred		0.60	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.35
gMVP		0.56
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

hg19: chr3-119528958;