rs2918417

Positions:

• chr5-143346605-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.1185-32437G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.284 in 152,014 control chromosomes in the GnomAD database, including 6,353 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 0.28 (6353 hom., cov: 32)
• Consequence: NR3C1 NM_000176.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.141

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=-0.93).
• 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	Protein	UniProt
NR3C1	NM_000176.3	c.1185-32437G>A		intron_variant		ENST00000394464.7	NP_000167.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR3C1	ENST00000394464.7	c.1185-32437G>A		intron_variant		1	NM_000176.3	ENSP00000377977	A1

Frequencies

GnomAD3 genomes AF: 0.283 AC: 43056 AN: 151896 Hom.: 6350 Cov.: 32

Gnomad AFR AF: 0.283

Gnomad AMI AF: 0.330

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.0957

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.281

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.323

Gnomad OTH AF: 0.277

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.283 AC: 43096 AN: 152014 Hom.: 6353 Cov.: 32 AF XY: 0.278 AC XY: 20657 AN XY: 74316

Gnomad4 AFR AF: 0.283

Gnomad4 AMR AF: 0.199

Gnomad4 ASJ AF: 0.293

Gnomad4 EAS AF: 0.0957

Gnomad4 SAS AF: 0.194

Gnomad4 FIN AF: 0.281

Gnomad4 NFE AF: 0.323

Gnomad4 OTH AF: 0.276

Alfa AF: 0.306 Hom.: 12444

Bravo AF: 0.276

Asia WGS AF: 0.168 AC: 584 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	4.6
DANN	Benign	0.29

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: rs2918417; hg19: chr5-142726170;