rs3814055

Variant names:

• chr3-119781188-C-T
• rs3814055
• ENST00000466380.6:c.-1135C>T

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

The ENST00000466380.6(NR1I2):c.-1135C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. Note: ENST00000466380.6 is not a MANE Select or MANE Plus Clinical transcript for NR1I2; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. The variant allele was found at a cumulative frequency of 0.352 (AC=53,604) in the gnomAD database across 152,196 control chromosomes, including 9,775 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.382. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.35 (9767 hom., cov: 33)
  • Exomes 𝑓: 0.36 (8 hom.)
• Consequence: NR1I2 ENST00000466380.6 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.03
• Publications: 37 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

ENSG00000285585 (HGNC:):

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); No splicing predictor data available.; Germline computational verdict: benign (Strong).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.3817 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: ENST00000466380.6. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	NR1I2 ENST00000466380.6	TSL:1	c.-1135C>T	5_prime_UTR	Exon 1 of 9	Prot: ENSP00000420297.2 UniProt:
	ENSG00000285585 ENST00000648112.1		c.*2-26041C>T	intron	Intron 17 of 17	Prot: ENSP00000497876.1 UniProt:

NR1I2 ENST00000466380.6

TSL:1

HGVSc / HGVSpc.-1135C>T

Exon rankExon 1 of 9

5_prime_UTR

Prot: ENSP00000420297.2UniProt: O75469-4

ENSG00000285585 ENST00000648112.1

HGVSc / HGVSpc.*2-26041C>T

Exon rankIntron 17 of 17

intron

Prot: ENSP00000497876.1UniProt: Q7Z4T9-7

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.352	AC:53532	Hom:9764	AN:151956	Cov:33
GnomAD4 exome	AF: 0.361	AC:44	Hom:8	AN:122	Cov:0
GnomAD4 genome	AF: 0.352	AC:53560	Hom:9767	AN:152074	Cov:33
TOPMed (Bravo)	AF: 0.348	AC:92143	Hom:16511	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.375	AC:269823	Hom:51391	AN:718600	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.358	AC:839	Hom:161	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.230	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.390	AC:117	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.272	AC:946	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.255	AC:1844	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.409	AC:72	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.270	AC:33215	Hom:4561	AN:122810	Cov:
Turkish Variome	AF: 0.411	AC:635	Hom:127	AN:1546	Cov:
UK10K	AF: 0.381	AC:2883	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.220	AC:1972	Hom:204	AN:8960	Cov:

Showing 15 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.137	3118	22722	0.0639	1866	29216

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	5.6
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.6
DANN	Benign	0.72
GPN-Star LLR	N/A	-0.85
GPN-Star score	N/A	0.85
PhyloP100	Benign	-1.0

Showing 7 of 7 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0

Showing 1 of 1 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs3814055;

hg19: chr3-119500035;

COSMIC: COSV114894675;

COSMIC: COSV114894675;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar