Genetic Variant NM_003889.4:c.-22-7178C>T (chr3-119800051-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003889.4(NR1I2):c.-22-7178C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.622 in 152,008 control chromosomes in the GnomAD database, including 29,578 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.62 ( 29578 hom., cov: 32)

Consequence

NR1I2
NM_003889.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.287

Publications

6 publications found

Variant links:

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

NR1I2 links:

ENSG00000285585 (HGNC:):

ENSG00000285585 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.98).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.617 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
NR1I2	NM_003889.4 link	c.-22-7178C>T	intron_variant	Intron 1 of 8	ENST00000393716.8	NP_003880.3	O75469-1
NR1I2	NM_022002.3 link	c.96-7178C>T	intron_variant	Intron 1 of 8		NP_071285.1	O75469-7F1D8P9
NR1I2	NM_033013.3 link	c.-22-7178C>T	intron_variant	Intron 1 of 8		NP_148934.1	O75469-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR1I2	ENST00000393716.8 link	c.-22-7178C>T		intron_variant	Intron 1 of 8	1	NM_003889.4	ENSP00000377319.3		O75469-1J3KPQ3
ENSG00000285585	ENST00000648112.1 link	c.*2-7178C>T		intron_variant	Intron 17 of 17			ENSP00000497876.1

Frequencies

GnomAD3 genomes

AF:

0.622

AC:

94499

AN:

151890

Hom.:

29554

Cov.:

show subpopulations

Gnomad AFR

AF:

0.621

Gnomad AMI

AF:

0.688

Gnomad AMR

AF:

0.555

Gnomad ASJ

AF:

0.673

Gnomad EAS

AF:

0.635

Gnomad SAS

AF:

0.614

Gnomad FIN

AF:

0.698

Gnomad MID

AF:

0.713

Gnomad NFE

AF:

0.622

Gnomad OTH

AF:

0.600

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.622

AC:

94576

AN:

152008

Hom.:

29578

Cov.:

AF XY:

0.625

AC XY:

46465

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.621

AC:

25749

AN:

41442

American (AMR)

AF:

0.555

AC:

8466

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.673

AC:

2337

AN:

3470

East Asian (EAS)

AF:

0.634

AC:

3280

AN:

5170

South Asian (SAS)

AF:

0.614

AC:

2962

AN:

4822

European-Finnish (FIN)

AF:

0.698

AC:

7369

AN:

10556

Middle Eastern (MID)

AF:

0.705

AC:

206

AN:

292

European-Non Finnish (NFE)

AF:

0.622

AC:

42310

AN:

67972

Other (OTH)

AF:

0.602

AC:

1271

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1827

3653

5480

7306

9133

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

776

1552

2328

3104

3880

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.615

Hom.:

46182

Bravo

AF:

0.610

Asia WGS

AF:

0.615

AC:

2143

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

1.3

(source)

DANN

Benign

0.80

PhyloP100

-0.29

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over