rs258751

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000176.3(NR3C1):c.2034C>T(p.Asp678=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00945 in 1,612,806 control chromosomes in the GnomAD database, including 591 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.036 ( 272 hom., cov: 31)

Exomes 𝑓: 0.0067 ( 319 hom. )

Consequence

NR3C1
NM_000176.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.0830

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant 5-143282715-G-A is Benign according to our data. Variant chr5-143282715-G-A is described in ClinVar as [Benign]. Clinvar id is 351367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.083 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR3C1	NM_000176.3 linkuse as main transcript	c.2034C>T	p.Asp678=	synonymous_variant	8/9	ENST00000394464.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR3C1	ENST00000394464.7 linkuse as main transcript	c.2034C>T	p.Asp678=	synonymous_variant	8/9	1	NM_000176.3	A1	P04150-1

Frequencies

GnomAD3 genomes

AF:

0.0358

AC:

5409

AN:

151276

Hom.:

275

Cov.:

show subpopulations

Gnomad AFR

AF:

0.108

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0110

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0716

Gnomad SAS

AF:

0.0108

Gnomad FIN

AF:

0.0229

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00100

Gnomad OTH

AF:

0.0237

GnomAD3 exomes

AF:

0.0166

AC:

4176

AN:

250894

Hom.:

143

AF XY:

0.0145

AC XY:

1968

AN XY:

135562

show subpopulations

Gnomad AFR exome

AF:

0.110

Gnomad AMR exome

AF:

0.00620

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0702

Gnomad SAS exome

AF:

0.00977

Gnomad FIN exome

AF:

0.0205

Gnomad NFE exome

AF:

0.000821

Gnomad OTH exome

AF:

0.00817

GnomAD4 exome

AF:

0.00672

AC:

9824

AN:

1461458

Hom.:

319

Cov.:

AF XY:

0.00641

AC XY:

4659

AN XY:

727020

show subpopulations

Gnomad4 AFR exome

AF:

0.109

Gnomad4 AMR exome

AF:

0.00718

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0699

Gnomad4 SAS exome

AF:

0.00907

Gnomad4 FIN exome

AF:

0.0194

Gnomad4 NFE exome

AF:

0.000397

Gnomad4 OTH exome

AF:

0.0127

GnomAD4 genome

AF:

0.0357

AC:

5410

AN:

151348

Hom.:

272

Cov.:

AF XY:

0.0359

AC XY:

2654

AN XY:

73894

show subpopulations

Gnomad4 AFR

AF:

0.108

Gnomad4 AMR

AF:

0.0109

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0715

Gnomad4 SAS

AF:

0.0105

Gnomad4 FIN

AF:

0.0229

Gnomad4 NFE

AF:

0.00100

Gnomad4 OTH

AF:

0.0235

Alfa

AF:

0.00790

Hom.:

108

Bravo

AF:

0.0377

Asia WGS

AF:

0.0530

AC:

183

AN:

3478

EpiCase

AF:

0.000546

EpiControl

AF:

0.00113

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glucocorticoid resistance

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 23, 2024

- -

NR3C1-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 09, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

8.2

DANN

Benign

0.45

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over