5-143310259-C-G

Position:

• chr5-143310259-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000176.3(NR3C1):​c.1352-46G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00769 in 1,324,634 control chromosomes in the GnomAD database, including 53 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 0.0063 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0079 (49 hom.)
• Consequence: NR3C1 NM_000176.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.567

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00628 (956/152254) while in subpopulation NFE AF= 0.00891 (606/68012). AF 95% confidence interval is 0.00832. There are 4 homozygotes in gnomad4. There are 502 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR3C1	NM_000176.3	c.1352-46G>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.1352-46G>C		intron_variant		1	NM_000176.3	ENSP00000377977.2

Frequencies

GnomAD3 genomes AF: 0.00629 AC: 957 AN: 152136 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00167

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.0192

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00891

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00643 AC: 1555 AN: 241952 Hom.: 11 AF XY: 0.00664 AC XY: 874 AN XY: 131548

Gnomad AFR exome AF: 0.00171

Gnomad AMR exome AF: 0.00193

Gnomad ASJ exome AF: 0.00172

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00209

Gnomad FIN exome AF: 0.0207

Gnomad NFE exome AF: 0.00895

Gnomad OTH exome AF: 0.00401

GnomAD4 exome AF: 0.00787 AC: 9231 AN: 1172380 Hom.: 49 Cov.: 15 AF XY: 0.00782 AC XY: 4669 AN XY: 596974

Gnomad4 AFR exome AF: 0.00136

Gnomad4 AMR exome AF: 0.00188

Gnomad4 ASJ exome AF: 0.00161

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00234

Gnomad4 FIN exome AF: 0.0184

Gnomad4 NFE exome AF: 0.00900

Gnomad4 OTH exome AF: 0.00593

GnomAD4 genome AF: 0.00628 AC: 956 AN: 152254 Hom.: 4 Cov.: 32 AF XY: 0.00674 AC XY: 502 AN XY: 74444

Gnomad4 AFR AF: 0.00166

Gnomad4 AMR AF: 0.00275

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.0192

Gnomad4 NFE AF: 0.00891

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00595 Hom.: 1

Bravo AF: 0.00459

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.45
DANN	Benign	0.35

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: rs61753484; hg19: chr5-142689824;