rs41423247

Variant names:

• chr5-143399010-G-C
• rs41423247
• NM_000176.3:c.1184+646C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000176.3(NR3C1):​c.1184+646C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 152,026 control chromosomes in the GnomAD database, including 7,823 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 0.31 (7823 hom., cov: 32)
• Consequence: NR3C1 NM_000176.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.348

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.368 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR3C1	NM_000176.3	c.1184+646C>G		intron_variant	Intron 2 of 8	ENST00000394464.7	NP_000167.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR3C1	ENST00000394464.7	c.1184+646C>G		intron_variant	Intron 2 of 8	1	NM_000176.3	ENSP00000377977.2

Frequencies

GnomAD3 genomes AF: 0.309 AC: 46918 AN: 151906 Hom.: 7819 Cov.: 32

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.525

Gnomad AMR AF: 0.257

Gnomad ASJ AF: 0.244

Gnomad EAS AF: 0.225

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.421

Gnomad MID AF: 0.264

Gnomad NFE AF: 0.372

Gnomad OTH AF: 0.283

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

GnomAD4 genome AF: 0.309 AC: 46951 AN: 152026 Hom.: 7823 Cov.: 32 AF XY: 0.306 AC XY: 22776 AN XY: 74330

Gnomad4 AFR AF: 0.219 AC: 0.219048 AN: 0.219048

Gnomad4 AMR AF: 0.256 AC: 0.256283 AN: 0.256283

Gnomad4 ASJ AF: 0.244 AC: 0.243952 AN: 0.243952

Gnomad4 EAS AF: 0.224 AC: 0.224198 AN: 0.224198

Gnomad4 SAS AF: 0.224 AC: 0.224088 AN: 0.224088

Gnomad4 FIN AF: 0.421 AC: 0.421277 AN: 0.421277

Gnomad4 NFE AF: 0.372 AC: 0.371853 AN: 0.371853

Gnomad4 OTH AF: 0.282 AC: 0.282464 AN: 0.282464

Alfa AF: 0.339 Hom.: 1119

Bravo AF: 0.295

Asia WGS AF: 0.260 AC: 906 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.2
DANN	Benign	0.39
Mutation Taster		=100/0	polymorphism (auto)

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: rs41423247; hg19: chr5-142778575;