rs6188

Variant names:

• chr5-143300779-C-A
• rs6188
• NM_000176.3:c.1469-16G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.617
• Publications: 24 publications found

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

ENSG00000300303 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 1326986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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	c.1469-16G>T		intron_variant	Intron 4 of 8	ENST00000394464.7	NP_000167.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR3C1	ENST00000394464.7	c.1469-16G>T		intron_variant	Intron 4 of 8	1	NM_000176.3	ENSP00000377977.2

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43674 AN: 151808 Hom.: 6541 Cov.: 32

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

GnomAD2 exomes AF: 0.257 AC: 63799 AN: 247780 AF XY: 0.262

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 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.: 32 AF XY: 0.300 AC XY: 217300 AN XY: 725176

African (AFR) AF: 0.301 AC: 10025 AN: 33290

American (AMR) AF: 0.149 AC: 6629 AN: 44514

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 7653 AN: 26048

East Asian (EAS) AF: 0.0892 AC: 3541 AN: 39676

South Asian (SAS) AF: 0.204 AC: 17567 AN: 85958

European-Finnish (FIN) AF: 0.289 AC: 15373 AN: 53252

Middle Eastern (MID) AF: 0.303 AC: 1672 AN: 5518

European-Non Finnish (NFE) AF: 0.325 AC: 360106 AN: 1108944

Other (OTH) AF: 0.297 AC: 17883 AN: 60194

GnomAD4 genome AF: 0.288 AC: 43719 AN: 151926 Hom.: 6549 Cov.: 32 AF XY: 0.282 AC XY: 20922 AN XY: 74234

African (AFR) AF: 0.299 AC: 12372 AN: 41408

American (AMR) AF: 0.200 AC: 3050 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 1013 AN: 3466

East Asian (EAS) AF: 0.0950 AC: 493 AN: 5190

South Asian (SAS) AF: 0.194 AC: 936 AN: 4824

European-Finnish (FIN) AF: 0.280 AC: 2939 AN: 10496

Middle Eastern (MID) AF: 0.318 AC: 93 AN: 292

European-Non Finnish (NFE) AF: 0.323 AC: 21930 AN: 67964

Other (OTH) AF: 0.280 AC: 592 AN: 2114

Alfa AF: 0.305 Hom.: 9554

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

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
PhyloP100		-0.62
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6188; hg19: chr5-142680344; COSMIC: COSV51543253;