rs2918419

Positions:

• chr5-143342788-T-C
• chr5-143342788-T-G

Variant summary

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

The NM_000176.3(NR3C1):​c.1185-28620A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 152,006 control chromosomes in the GnomAD database, including 1,860 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 (1860 hom., cov: 32)
• Consequence: NR3C1 NM_000176.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.56

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 (AFR) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR3C1	NM_000176.3	c.1185-28620A>G		intron_variant		ENST00000394464.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR3C1	ENST00000394464.7	c.1185-28620A>G		intron_variant		1	NM_000176.3	A1

Frequencies

GnomAD3 genomes AF: 0.149 AC: 22578 AN: 151888 Hom.: 1856 Cov.: 32

Gnomad AFR AF: 0.177

Gnomad AMI AF: 0.242

Gnomad AMR AF: 0.0818

Gnomad ASJ AF: 0.0623

Gnomad EAS AF: 0.0722

Gnomad SAS AF: 0.0338

Gnomad FIN AF: 0.206

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.119

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

GnomAD4 genome AF: 0.149 AC: 22612 AN: 152006 Hom.: 1860 Cov.: 32 AF XY: 0.147 AC XY: 10927 AN XY: 74316

Gnomad4 AFR AF: 0.177

Gnomad4 AMR AF: 0.0817

Gnomad4 ASJ AF: 0.0623

Gnomad4 EAS AF: 0.0722

Gnomad4 SAS AF: 0.0328

Gnomad4 FIN AF: 0.206

Gnomad4 NFE AF: 0.156

Gnomad4 OTH AF: 0.118

Alfa AF: 0.140 Hom.: 1494

Bravo AF: 0.141

Asia WGS AF: 0.0740 AC: 256 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.086
DANN	Benign	0.55

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: rs2918419; hg19: chr5-142722353; COSMIC: COSV51547305;