dbSNP rs860457: NR3C1:c.1468+1339A>G (chr5-143308758-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_000176.3(NR3C1):c.1468+1339A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.279 in 152,098 control chromosomes in the GnomAD database, including 6,175 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 0.28 ( 6175 hom., cov: 32)

Consequence

NR3C1
NM_000176.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.803

Publications

16 publications found

Variant links:

Genes affected

NR3C1 (HGNC:7978): (nuclear receptor subfamily 3 group C member 1) This gene encodes glucocorticoid receptor, which can function both as a transcription factor that binds to glucocorticoid response elements in the promoters of glucocorticoid responsive genes to activate their transcription, and as a regulator of other transcription factors. This receptor is typically found in the cytoplasm, but upon ligand binding, is transported into the nucleus. It is involved in inflammatory responses, cellular proliferation, and differentiation in target tissues. Mutations in this gene are associated with generalized glucocorticoid resistance. Alternative splicing of this gene results in transcript variants encoding either the same or different isoforms. Additional isoforms resulting from the use of alternate in-frame translation initiation sites have also been described, and shown to be functional, displaying diverse cytoplasm-to-nucleus trafficking patterns and distinct transcriptional activities (PMID:15866175). [provided by RefSeq, Feb 2011]

NR3C1 Gene-Disease associations (from GenCC):

glucocorticoid resistance
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

NR3C1 links:

ENSG00000300303 (HGNC:):

ENSG00000300303 links:

Genome browser will be placed here

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=-0.9).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.32 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR3C1	NM_000176.3 link	c.1468+1339A>G		intron_variant	Intron 4 of 8	ENST00000394464.7	NP_000167.1	P04150-1F1D8N4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR3C1	ENST00000394464.7 link	c.1468+1339A>G		intron_variant	Intron 4 of 8	1	NM_000176.3	ENSP00000377977.2		P04150-1

Frequencies

GnomAD3 genomes

AF:

0.279

AC:

42391

AN:

151980

Hom.:

6176

Cov.:

show subpopulations

Gnomad AFR

AF:

0.268

Gnomad AMI

AF:

0.331

Gnomad AMR

AF:

0.198

Gnomad ASJ

AF:

0.300

Gnomad EAS

AF:

0.0748

Gnomad SAS

AF:

0.193

Gnomad FIN

AF:

0.280

Gnomad MID

AF:

0.326

Gnomad NFE

AF:

0.324

Gnomad OTH

AF:

0.272

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

GnomAD4 genome

AF:

0.279

AC:

42423

AN:

152098

Hom.:

6175

Cov.:

AF XY:

0.273

AC XY:

20298

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.268

AC:

11119

AN:

41460

American (AMR)

AF:

0.198

AC:

3025

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.300

AC:

1042

AN:

3470

East Asian (EAS)

AF:

0.0748

AC:

388

AN:

5188

South Asian (SAS)

AF:

0.192

AC:

927

AN:

4822

European-Finnish (FIN)

AF:

0.280

AC:

2956

AN:

10574

Middle Eastern (MID)

AF:

0.323

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.324

AC:

22002

AN:

67978

Other (OTH)

AF:

0.269

AC:

567

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1525

3050

4574

6099

7624

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

432

864

1296

1728

2160

<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:

0.293

Hom.:

9869

Bravo

AF:

0.272

Asia WGS

AF:

0.154

AC:

535

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.67

(source)

DANN

Benign

0.70

PhyloP100

-0.80

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