Genetic Variant NM_003889.4:c.-23+10228C>A (chr3-119792528-C-A) – 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.-23+10228C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 998,920 control chromosomes in the GnomAD database, including 34,276 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 0.23 ( 5042 hom., cov: 32)

Exomes 𝑓: 0.25 ( 29234 hom. )

Consequence

NR1I2
NM_003889.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.43

Publications

4 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 links:

ENSG00000285585 (HGNC:):

ENSG00000285585 links:

PHB1P8 (HGNC:39287): (PHB1 pseudogene 8)

PHB1P8 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=-0.67).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.351 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
NR1I2	NM_003889.4 link	c.-23+10228C>A	intron_variant	Intron 1 of 8	ENST00000393716.8	NP_003880.3
PHB1P8		n.119792528C>A	intragenic_variant
NR1I2	NM_022002.3 link	c.95+9676C>A	intron_variant	Intron 1 of 8		NP_071285.1
NR1I2	NM_033013.3 link	c.-23+10228C>A	intron_variant	Intron 1 of 8		NP_148934.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR1I2	ENST00000393716.8 link	c.-23+10228C>A		intron_variant	Intron 1 of 8	1	NM_003889.4	ENSP00000377319.3
ENSG00000285585	ENST00000648112.1 link	c.*2-14701C>A		intron_variant	Intron 17 of 17			ENSP00000497876.1

Frequencies

GnomAD3 genomes

AF:

0.232

AC:

35330

AN:

152000

Hom.:

5040

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0823

Gnomad AMI

AF:

0.250

Gnomad AMR

AF:

0.353

Gnomad ASJ

AF:

0.191

Gnomad EAS

AF:

0.364

Gnomad SAS

AF:

0.306

Gnomad FIN

AF:

0.242

Gnomad MID

AF:

0.174

Gnomad NFE

AF:

0.282

Gnomad OTH

AF:

0.247

GnomAD4 exome

AF:

0.251

AC:

212874

AN:

846802

Hom.:

29234

Cov.:

AF XY:

0.255

AC XY:

111386

AN XY:

437178

show subpopulations

African (AFR)

AF:

0.0684

AC:

1511

AN:

22088

American (AMR)

AF:

0.479

AC:

16433

AN:

34322

Ashkenazi Jewish (ASJ)

AF:

0.197

AC:

4213

AN:

21362

East Asian (EAS)

AF:

0.339

AC:

11034

AN:

32572

South Asian (SAS)

AF:

0.295

AC:

20020

AN:

67840

European-Finnish (FIN)

AF:

0.236

AC:

11069

AN:

46910

Middle Eastern (MID)

AF:

0.211

AC:

838

AN:

3964

European-Non Finnish (NFE)

AF:

0.239

AC:

138163

AN:

578544

Other (OTH)

AF:

0.245

AC:

9593

AN:

39200

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

7046

14092

21139

28185

35231

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2994

5988

8982

11976

14970

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.232

AC:

35338

AN:

152118

Hom.:

5042

Cov.:

AF XY:

0.233

AC XY:

17366

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.0822

AC:

3414

AN:

41542

American (AMR)

AF:

0.353

AC:

5392

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.191

AC:

663

AN:

3468

East Asian (EAS)

AF:

0.365

AC:

1883

AN:

5160

South Asian (SAS)

AF:

0.306

AC:

1472

AN:

4810

European-Finnish (FIN)

AF:

0.242

AC:

2561

AN:

10596

Middle Eastern (MID)

AF:

0.180

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.282

AC:

19152

AN:

67946

Other (OTH)

AF:

0.246

AC:

520

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1296

2592

3888

5184

6480

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

380

760

1140

1520

1900

<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:

0.252

Hom.:

661

Bravo

AF:

0.237

Asia WGS

AF:

0.325

AC:

1129

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

2.7

(source)

DANN

Benign

0.65

PhyloP100

3.4

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over