5-143400772-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_000176.3(NR3C1):c.68G>A(p.Arg23Lys) variant causes a missense change. The variant allele was found at a frequency of 0.024 in 1,614,144 control chromosomes in the GnomAD database, including 590 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 42 hom., cov: 32)

Exomes 𝑓: 0.025 ( 548 hom. )

Consequence

NR3C1
NM_000176.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.77

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 -18 ACMG points.

PM1

In a modified_residue Omega-N-methylarginine (size 0) in uniprot entity GCR_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.0039635897).

BP6

Variant 5-143400772-C-T is Benign according to our data. Variant chr5-143400772-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 351377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-143400772-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0166 (2535/152312) while in subpopulation NFE AF= 0.0274 (1863/68038). AF 95% confidence interval is 0.0263. There are 42 homozygotes in gnomad4. There are 1168 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 42 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR3C1	NM_000176.3 link	c.68G>A	p.Arg23Lys	missense_variant	Exon 2 of 9	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.68G>A	p.Arg23Lys	missense_variant	Exon 2 of 9	1	NM_000176.3	ENSP00000377977.2		P04150-1

Frequencies

GnomAD3 genomes

AF:

0.0166

AC:

2533

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00456

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00621

Gnomad ASJ

AF:

0.0184

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0139

Gnomad FIN

AF:

0.0208

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0274

Gnomad OTH

AF:

0.0124

GnomAD3 exomes

AF:

0.0183

AC:

4603

AN:

251468

Hom.:

AF XY:

0.0191

AC XY:

2595

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00443

Gnomad AMR exome

AF:

0.00676

Gnomad ASJ exome

AF:

0.0200

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0152

Gnomad FIN exome

AF:

0.0243

Gnomad NFE exome

AF:

0.0263

Gnomad OTH exome

AF:

0.0181

GnomAD4 exome

AF:

0.0248

AC:

36197

AN:

1461832

Hom.:

548

Cov.:

AF XY:

0.0245

AC XY:

17834

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.00355

Gnomad4 AMR exome

AF:

0.00720

Gnomad4 ASJ exome

AF:

0.0195

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0152

Gnomad4 FIN exome

AF:

0.0223

Gnomad4 NFE exome

AF:

0.0283

Gnomad4 OTH exome

AF:

0.0202

GnomAD4 genome

AF:

0.0166

AC:

2535

AN:

152312

Hom.:

Cov.:

AF XY:

0.0157

AC XY:

1168

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00455

Gnomad4 AMR

AF:

0.00621

Gnomad4 ASJ

AF:

0.0184

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0143

Gnomad4 FIN

AF:

0.0208

Gnomad4 NFE

AF:

0.0274

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.0228

Hom.:

120

Bravo

AF:

0.0149

TwinsUK

AF:

0.0270

AC:

100

ALSPAC

AF:

0.0304

AC:

117

ESP6500AA

AF:

0.00431

AC:

ESP6500EA

AF:

0.0285

AC:

245

ExAC

AF:

0.0178

AC:

2165

Asia WGS

AF:

0.00751

AC:

AN:

3478

EpiCase

AF:

0.0253

EpiControl

AF:

0.0254

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Glucocorticoid resistance

Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

NR3C1-related disorder

Benign:1

Jul 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.31

T;T;.;.;.;.;.;T;T;T;T;T;T

Eigen

Benign

0.044

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.58

.;T;T;T;.;.;T;.;.;.;.;T;T

MetaRNN

Benign

0.0040

T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.54

MutationAssessor

Benign

1.8

L;L;L;L;L;L;L;L;.;.;.;.;.

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.22

N;N;N;N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.14

Sift

Benign

0.035

D;D;D;D;D;D;D;D;T;T;T;T;T

Sift4G

Benign

0.98

T;T;T;T;T;T;T;T;.;.;.;.;T

Polyphen

0.29

B;B;.;.;.;.;.;B;.;.;.;.;.

Vest4

0.14

MPC

0.055

ClinPred

0.018

GERP RS

5.2

Varity_R

0.18

gMVP

0.22

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