rs258813

chr5-143295125-G-A

Variant summary

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

The NM_000176.3(NR3C1):c.2023+335C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.317 in 984,728 control chromosomes in the GnomAD database, including 49,905 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 0.29 (6528 hom., cov: 32)
  • Exomes 𝑓: 0.32 (43377 hom.)
• Consequence: NR3C1 NM_000176.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.741

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=-0.98).
• 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/exons	MANE	UniProt
NR3C1	NM_000176.3	c.2023+335C>T		intron_variant		ENST00000394464.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR3C1	ENST00000394464.7	c.2023+335C>T		intron_variant		1	NM_000176.3	A1

Frequencies

GnomAD3 genomes AF: 0.287 AC: 43603 AN: 151820 Hom.: 6521 Cov.: 32

Gnomad AFR AF: 0.297

Gnomad AMI AF: 0.331

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.294

Gnomad EAS AF: 0.0959

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.280

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.322

Gnomad OTH AF: 0.280

GnomAD4 exome AF: 0.322 AC: 268155 AN: 832788 Hom.: 43377 Cov.: 31 AF XY: 0.322 AC XY: 123884 AN XY: 384568

Gnomad4 AFR exome AF: 0.303

Gnomad4 AMR exome AF: 0.203

Gnomad4 ASJ exome AF: 0.291

Gnomad4 EAS exome AF: 0.113

Gnomad4 SAS exome AF: 0.202

Gnomad4 FIN exome AF: 0.319

Gnomad4 NFE exome AF: 0.327

Gnomad4 OTH exome AF: 0.304

GnomAD4 genome AF: 0.287 AC: 43646 AN: 151940 Hom.: 6528 Cov.: 32 AF XY: 0.281 AC XY: 20878 AN XY: 74244

Gnomad4 AFR AF: 0.298

Gnomad4 AMR AF: 0.200

Gnomad4 ASJ AF: 0.294

Gnomad4 EAS AF: 0.0959

Gnomad4 SAS AF: 0.194

Gnomad4 FIN AF: 0.280

Gnomad4 NFE AF: 0.322

Gnomad4 OTH AF: 0.279

Alfa AF: 0.308 Hom.: 12101

Bravo AF: 0.281

Asia WGS AF: 0.171 AC: 596 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
Cadd	Benign	1.9
Dann	Benign	0.10

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: rs258813; hg19: chr5-142674690; COSMIC: COSV51545682;