Genetic Variant NM_000176.3:c.1184+646C>G (chr5-143399010-G-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.1184+646C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 152,026 control chromosomes in the GnomAD database, including 7,823 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 0.31 ( 7823 hom., cov: 32)

Consequence

NR3C1
NM_000176.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.348

Publications

219 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:

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=-0.84).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.368 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR3C1	NM_000176.3 link	c.1184+646C>G		intron_variant	Intron 2 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.1184+646C>G		intron_variant	Intron 2 of 8	1	NM_000176.3	ENSP00000377977.2		P04150-1

Frequencies

GnomAD3 genomes

AF:

0.309

AC:

46918

AN:

151906

Hom.:

7819

Cov.:

show subpopulations

Gnomad AFR

AF:

0.219

Gnomad AMI

AF:

0.525

Gnomad AMR

AF:

0.257

Gnomad ASJ

AF:

0.244

Gnomad EAS

AF:

0.225

Gnomad SAS

AF:

0.226

Gnomad FIN

AF:

0.421

Gnomad MID

AF:

0.264

Gnomad NFE

AF:

0.372

Gnomad OTH

AF:

0.283

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

GnomAD4 genome

AF:

0.309

AC:

46951

AN:

152026

Hom.:

7823

Cov.:

AF XY:

0.306

AC XY:

22776

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.219

AC:

9087

AN:

41484

American (AMR)

AF:

0.256

AC:

3916

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.244

AC:

847

AN:

3472

East Asian (EAS)

AF:

0.224

AC:

1160

AN:

5174

South Asian (SAS)

AF:

0.224

AC:

1081

AN:

4824

European-Finnish (FIN)

AF:

0.421

AC:

4447

AN:

10556

Middle Eastern (MID)

AF:

0.279

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.372

AC:

25257

AN:

67922

Other (OTH)

AF:

0.282

AC:

596

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1640

3280

4921

6561

8201

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

464

928

1392

1856

2320

<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:

0.339

Hom.:

1119

Bravo

AF:

0.295

Asia WGS

AF:

0.260

AC:

906

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.2

(source)

DANN

Benign

0.39

PhyloP100

-0.35

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