rs4634384

chr5-143401132-C-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR3C1	NM_000176.3	c.-13-280G>A		intron_variant		ENST00000394464.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR3C1	ENST00000394464.7	c.-13-280G>A		intron_variant		1	NM_000176.3	A1

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

Gnomad4 AFR exome AF: 0.563

Gnomad4 AMR exome AF: 0.641

Gnomad4 ASJ exome AF: 0.511

Gnomad4 EAS exome AF: 0.782

Gnomad4 SAS exome AF: 0.598

Gnomad4 FIN exome AF: 0.493

Gnomad4 NFE exome AF: 0.465

Gnomad4 OTH exome AF: 0.511

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

Gnomad4 AFR AF: 0.564

Gnomad4 AMR AF: 0.617

Gnomad4 ASJ AF: 0.523

Gnomad4 EAS AF: 0.757

Gnomad4 SAS AF: 0.614

Gnomad4 FIN AF: 0.497

Gnomad4 NFE AF: 0.462

Gnomad4 OTH AF: 0.533

Alfa AF: 0.500 Hom.: 2383

Bravo AF: 0.536

Asia WGS AF: 0.638 AC: 2215 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	9.4
Dann	Benign	0.86

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

Other links and lift over

dbSNP: rs4634384; hg19: chr5-142780697;