rs4986593

Positions:

• chr5-143314281-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000176.3(NR3C1):​c.1185-113T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 1,107,618 control chromosomes in the GnomAD database, including 23,839 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 0.16 (2419 hom., cov: 32)
  • Exomes 𝑓: 0.21 (21420 hom.)
• Consequence: NR3C1 NM_000176.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.699

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=-0.75).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR3C1	NM_000176.3	c.1185-113T>C		intron_variant		ENST00000394464.7	NP_000167.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR3C1	ENST00000394464.7	c.1185-113T>C		intron_variant		1	NM_000176.3	ENSP00000377977	A1

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24643 AN: 152082 Hom.: 2419 Cov.: 32

Gnomad AFR AF: 0.0465

Gnomad AMI AF: 0.282

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.183

Gnomad EAS AF: 0.181

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.217

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.214

Gnomad OTH AF: 0.162

GnomAD4 exome AF: 0.211 AC: 201461 AN: 955418 Hom.: 21420 AF XY: 0.211 AC XY: 103411 AN XY: 489044

Gnomad4 AFR exome AF: 0.0473

Gnomad4 AMR exome AF: 0.194

Gnomad4 ASJ exome AF: 0.192

Gnomad4 EAS exome AF: 0.162

Gnomad4 SAS exome AF: 0.210

Gnomad4 FIN exome AF: 0.221

Gnomad4 NFE exome AF: 0.221

Gnomad4 OTH exome AF: 0.196

GnomAD4 genome AF: 0.162 AC: 24642 AN: 152200 Hom.: 2419 Cov.: 32 AF XY: 0.161 AC XY: 12009 AN XY: 74412

Gnomad4 AFR AF: 0.0464

Gnomad4 AMR AF: 0.174

Gnomad4 ASJ AF: 0.183

Gnomad4 EAS AF: 0.180

Gnomad4 SAS AF: 0.198

Gnomad4 FIN AF: 0.217

Gnomad4 NFE AF: 0.214

Gnomad4 OTH AF: 0.163

Alfa AF: 0.203 Hom.: 3129

Bravo AF: 0.156

Asia WGS AF: 0.199 AC: 693 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.18
DANN	Benign	0.80

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: rs4986593; hg19: chr5-142693846;