chr5-143293832-A-G

Position:

• chr5-143293832-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.2023+1628T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 926,686 control chromosomes in the GnomAD database, including 18,718 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 (2398 hom., cov: 31)
  • Exomes 𝑓: 0.20 (16320 hom.)
• Consequence: NR3C1 NM_000176.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.399

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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.21 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR3C1	NM_000176.3	c.2023+1628T>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.2023+1628T>C		intron_variant		1	NM_000176.3	ENSP00000377977	A1

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24513 AN: 151480 Hom.: 2397 Cov.: 31

Gnomad AFR AF: 0.0470

Gnomad AMI AF: 0.284

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.182

Gnomad EAS AF: 0.181

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.219

Gnomad MID AF: 0.245

Gnomad NFE AF: 0.213

Gnomad OTH AF: 0.162

GnomAD4 exome AF: 0.202 AC: 156921 AN: 775104 Hom.: 16320 Cov.: 12 AF XY: 0.203 AC XY: 72836 AN XY: 359266

Gnomad4 AFR exome AF: 0.0304

Gnomad4 AMR exome AF: 0.176

Gnomad4 ASJ exome AF: 0.182

Gnomad4 EAS exome AF: 0.170

Gnomad4 SAS exome AF: 0.195

Gnomad4 FIN exome AF: 0.202

Gnomad4 NFE exome AF: 0.207

Gnomad4 OTH exome AF: 0.190

GnomAD4 genome AF: 0.162 AC: 24515 AN: 151582 Hom.: 2398 Cov.: 31 AF XY: 0.162 AC XY: 11973 AN XY: 74056

Gnomad4 AFR AF: 0.0469

Gnomad4 AMR AF: 0.175

Gnomad4 ASJ AF: 0.182

Gnomad4 EAS AF: 0.180

Gnomad4 SAS AF: 0.195

Gnomad4 FIN AF: 0.219

Gnomad4 NFE AF: 0.213

Gnomad4 OTH AF: 0.164

Alfa AF: 0.202 Hom.: 3110

Bravo AF: 0.156

Asia WGS AF: 0.195 AC: 678 AN: 3464

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.87
DANN	Benign	0.72

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: rs17209258; hg19: chr5-142673397; COSMIC: COSV51541189;