5-143402837-C-T

Position:

• chr5-143402837-C-T

Variant summary

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

The NM_001364185.1(NR3C1):​c.-249G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 985,192 control chromosomes in the GnomAD database, including 12,785 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 0.15 (1847 hom., cov: 33)
  • Exomes 𝑓: 0.16 (10938 hom.)
• Consequence: NR3C1 NM_001364185.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.885

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=-0.74).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR3C1	NM_000176.3	c.-14+374G>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.-14+374G>A		intron_variant		1	NM_000176.3	ENSP00000377977.2

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22538 AN: 152114 Hom.: 1841 Cov.: 33

Gnomad AFR AF: 0.176

Gnomad AMI AF: 0.242

Gnomad AMR AF: 0.0822

Gnomad ASJ AF: 0.0695

Gnomad EAS AF: 0.0653

Gnomad SAS AF: 0.0343

Gnomad FIN AF: 0.202

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.123

GnomAD4 exome AF: 0.160 AC: 133434 AN: 832962 Hom.: 10938 Cov.: 29 AF XY: 0.160 AC XY: 61445 AN XY: 384662

Gnomad4 AFR exome AF: 0.177

Gnomad4 AMR exome AF: 0.0813

Gnomad4 ASJ exome AF: 0.0687

Gnomad4 EAS exome AF: 0.0758

Gnomad4 SAS exome AF: 0.0335

Gnomad4 FIN exome AF: 0.209

Gnomad4 NFE exome AF: 0.165

Gnomad4 OTH exome AF: 0.141

GnomAD4 genome AF: 0.148 AC: 22573 AN: 152230 Hom.: 1847 Cov.: 33 AF XY: 0.146 AC XY: 10878 AN XY: 74432

Gnomad4 AFR AF: 0.177

Gnomad4 AMR AF: 0.0821

Gnomad4 ASJ AF: 0.0695

Gnomad4 EAS AF: 0.0653

Gnomad4 SAS AF: 0.0333

Gnomad4 FIN AF: 0.202

Gnomad4 NFE AF: 0.156

Gnomad4 OTH AF: 0.121

Alfa AF: 0.0976 Hom.: 164

Bravo AF: 0.141

Asia WGS AF: 0.0700 AC: 245 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	4.1
DANN	Benign	0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs10482614; hg19: chr5-142782402;