rs10482609

Positions:

• chr5-143403522-A-C

Variant summary

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

The ENST00000394464.7(NR3C1):​c.-325T>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00846 in 985,064 control chromosomes in the GnomAD database, including 74 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 0.010 (21 hom., cov: 33)
  • Exomes 𝑓: 0.0081 (53 hom.)
• Consequence: NR3C1 ENST00000394464.7 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.328

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=-0.51).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0104 (1575/151716) while in subpopulation SAS AF= 0.0363 (175/4820). AF 95% confidence interval is 0.0319. There are 21 homozygotes in gnomad4. There are 832 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 21 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR3C1	NM_000176.3	c.-325T>G		5_prime_UTR_variant	1/9	ENST00000394464.7	NP_000167.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR3C1	ENST00000394464.7	c.-325T>G		5_prime_UTR_variant	1/9	1	NM_000176.3	ENSP00000377977	A1

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1572 AN: 151608 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.00146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.0649

Gnomad EAS AF: 0.0220

Gnomad SAS AF: 0.0361

Gnomad FIN AF: 0.0128

Gnomad MID AF: 0.0258

Gnomad NFE AF: 0.00854

Gnomad OTH AF: 0.0177

GnomAD4 exome AF: 0.00811 AC: 6758 AN: 833348 Hom.: 53 Cov.: 32 AF XY: 0.00843 AC XY: 3246 AN XY: 384892

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.00609

Gnomad4 ASJ exome AF: 0.0623

Gnomad4 EAS exome AF: 0.0253

Gnomad4 SAS exome AF: 0.0371

Gnomad4 FIN exome AF: 0.00694

Gnomad4 NFE exome AF: 0.00687

Gnomad4 OTH exome AF: 0.0149

GnomAD4 genome AF: 0.0104 AC: 1575 AN: 151716 Hom.: 21 Cov.: 33 AF XY: 0.0112 AC XY: 832 AN XY: 74142

Gnomad4 AFR AF: 0.00145

Gnomad4 AMR AF: 0.0158

Gnomad4 ASJ AF: 0.0649

Gnomad4 EAS AF: 0.0221

Gnomad4 SAS AF: 0.0363

Gnomad4 FIN AF: 0.0128

Gnomad4 NFE AF: 0.00854

Gnomad4 OTH AF: 0.0185

Alfa AF: 0.00873 Hom.: 1

Bravo AF: 0.00997

Asia WGS AF: 0.0450 AC: 155 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Benign	0.78

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: rs10482609; hg19: chr5-142783087; COSMIC: COSV51542047; COSMIC: COSV51542047;