Genetic Variant NM_000176.3:c.1469-16G>T (chr5-143300779-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000176.3(NR3C1):c.1469-16G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 1,609,320 control chromosomes in the GnomAD database, including 75,742 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.29 ( 6549 hom., cov: 32)

Exomes 𝑓: 0.30 ( 69193 hom. )

Consequence

NR3C1
NM_000176.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.617

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 5-143300779-C-A is Benign according to our data. Variant chr5-143300779-C-A is described in ClinVar as [Benign]. Clinvar id is 1326986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-143300779-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR3C1	NM_000176.3 link	c.1469-16G>T		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.1469-16G>T		intron_variant	Intron 4 of 8	1	NM_000176.3	ENSP00000377977.2		P04150-1

Frequencies

GnomAD3 genomes

AF:

0.288

AC:

43674

AN:

151808

Hom.:

6541

Cov.:

show subpopulations

Gnomad AFR

AF:

0.298

Gnomad AMI

AF:

0.331

Gnomad AMR

AF:

0.200

Gnomad ASJ

AF:

0.292

Gnomad EAS

AF:

0.0950

Gnomad SAS

AF:

0.195

Gnomad FIN

AF:

0.280

Gnomad MID

AF:

0.322

Gnomad NFE

AF:

0.323

Gnomad OTH

AF:

0.281

GnomAD3 exomes

AF:

0.257

AC:

63799

AN:

247780

Hom.:

9127

AF XY:

0.262

AC XY:

35191

AN XY:

134286

show subpopulations

Gnomad AFR exome

AF:

0.296

Gnomad AMR exome

AF:

0.136

Gnomad ASJ exome

AF:

0.292

Gnomad EAS exome

AF:

0.0991

Gnomad SAS exome

AF:

0.207

Gnomad FIN exome

AF:

0.286

Gnomad NFE exome

AF:

0.319

Gnomad OTH exome

AF:

0.279

GnomAD4 exome

AF:

0.302

AC:

440449

AN:

1457394

Hom.:

69193

Cov.:

AF XY:

0.300

AC XY:

217300

AN XY:

725176

show subpopulations

Gnomad4 AFR exome

AF:

0.301

Gnomad4 AMR exome

AF:

0.149

Gnomad4 ASJ exome

AF:

0.294

Gnomad4 EAS exome

AF:

0.0892

Gnomad4 SAS exome

AF:

0.204

Gnomad4 FIN exome

AF:

0.289

Gnomad4 NFE exome

AF:

0.325

Gnomad4 OTH exome

AF:

0.297

GnomAD4 genome

AF:

0.288

AC:

43719

AN:

151926

Hom.:

6549

Cov.:

AF XY:

0.282

AC XY:

20922

AN XY:

74234

show subpopulations

Gnomad4 AFR

AF:

0.299

Gnomad4 AMR

AF:

0.200

Gnomad4 ASJ

AF:

0.292

Gnomad4 EAS

AF:

0.0950

Gnomad4 SAS

AF:

0.194

Gnomad4 FIN

AF:

0.280

Gnomad4 NFE

AF:

0.323

Gnomad4 OTH

AF:

0.280

Alfa

AF:

0.307

Hom.:

7485

Bravo

AF:

0.281

Asia WGS

AF:

0.170

AC:

592

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glucocorticoid resistance

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.12

DANN

Benign

0.54

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