rs4634384

Variant names:

• chr5-143401132-C-T
• rs4634384
• NM_000176.3:c.-13-280G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000176.3(NR3C1):​c.-13-280G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.521 in 450,808 control chromosomes in the GnomAD database, including 63,206 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 0.52 (21338 hom., cov: 32)
  • Exomes 𝑓: 0.52 (41868 hom.)
• Consequence: NR3C1 NM_000176.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.585
• Publications: 16 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: Labcorp Genetics (formerly Invitae), Orphanet, Laboratory for Molecular Medicine, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.737 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000176.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C1	NM_000176.3	MANE Select	c.-13-280G>A		intron	N/A	NP_000167.1	P04150-1
	NR3C1	NM_001024094.2		c.-13-280G>A		intron	N/A	NP_001019265.1	E5KQF6
	NR3C1	NM_001364183.2		c.-13-280G>A		intron	N/A	NP_001351112.1	P04150-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C1	ENST00000394464.7	TSL:1 MANE Select	c.-13-280G>A		intron	N/A	ENSP00000377977.2	P04150-1
	NR3C1	ENST00000231509.7	TSL:1	c.-13-280G>A		intron	N/A	ENSP00000231509.3	P04150-3
	NR3C1	ENST00000504572.5	TSL:1	c.-13-280G>A		intron	N/A	ENSP00000422518.1	P04150-3

Frequencies

GnomAD3 genomes AF: 0.525 AC: 79424 AN: 151394 Hom.: 21319 Cov.: 32

Gnomad AFR AF: 0.565

Gnomad AMI AF: 0.387

Gnomad AMR AF: 0.617

Gnomad ASJ AF: 0.523

Gnomad EAS AF: 0.756

Gnomad SAS AF: 0.612

Gnomad FIN AF: 0.497

Gnomad MID AF: 0.414

Gnomad NFE AF: 0.462

Gnomad OTH AF: 0.533

GnomAD4 exome AF: 0.519 AC: 155206 AN: 299296 Hom.: 41868 AF XY: 0.523 AC XY: 83299 AN XY: 159282

African (AFR) AF: 0.563 AC: 5202 AN: 9246

American (AMR) AF: 0.641 AC: 8912 AN: 13898

Ashkenazi Jewish (ASJ) AF: 0.511 AC: 4683 AN: 9164

East Asian (EAS) AF: 0.782 AC: 14545 AN: 18596

South Asian (SAS) AF: 0.598 AC: 22920 AN: 38332

European-Finnish (FIN) AF: 0.493 AC: 6886 AN: 13960

Middle Eastern (MID) AF: 0.497 AC: 659 AN: 1326

European-Non Finnish (NFE) AF: 0.465 AC: 82667 AN: 177686

Other (OTH) AF: 0.511 AC: 8732 AN: 17088

GnomAD4 genome AF: 0.525 AC: 79486 AN: 151512 Hom.: 21338 Cov.: 32 AF XY: 0.531 AC XY: 39339 AN XY: 74016

African (AFR) AF: 0.564 AC: 23277 AN: 41240

American (AMR) AF: 0.617 AC: 9395 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.523 AC: 1808 AN: 3460

East Asian (EAS) AF: 0.757 AC: 3888 AN: 5136

South Asian (SAS) AF: 0.614 AC: 2959 AN: 4822

European-Finnish (FIN) AF: 0.497 AC: 5210 AN: 10478

Middle Eastern (MID) AF: 0.404 AC: 118 AN: 292

European-Non Finnish (NFE) AF: 0.462 AC: 31355 AN: 67840

Other (OTH) AF: 0.533 AC: 1124 AN: 2110

Alfa AF: 0.503 Hom.: 2503

Bravo AF: 0.536

Asia WGS AF: 0.638 AC: 2215 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	9.4
DANN	Benign	0.86
PhyloP100		0.58
PromoterAI		0.0079	Neutral
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4634384;

hg19: chr5-142780697;