rs4986593

Variant names:

• chr5-143314281-A-G
• rs4986593
• NM_000176.3:c.1185-113T>C

Variant summary

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

The NM_000176.3(NR3C1):​c.1185-113T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 1,107,618 control chromosomes in the GnomAD database, including 23,839 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 (2419 hom., cov: 32)
  • Exomes 𝑓: 0.21 (21420 hom.)
• Consequence: NR3C1 NM_000176.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.699
• Publications: 14 publications found

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 Gene-Disease associations (from GenCC):

• glucocorticoid resistance

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR3C1	NM_000176.3	c.1185-113T>C		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.1185-113T>C		intron_variant	Intron 2 of 8	1	NM_000176.3	ENSP00000377977.2

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24643 AN: 152082 Hom.: 2419 Cov.: 32

Gnomad AFR AF: 0.0465

Gnomad AMI AF: 0.282

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.183

Gnomad EAS AF: 0.181

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.217

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.214

Gnomad OTH AF: 0.162

GnomAD4 exome AF: 0.211 AC: 201461 AN: 955418 Hom.: 21420 AF XY: 0.211 AC XY: 103411 AN XY: 489044

African (AFR) AF: 0.0473 AC: 1073 AN: 22662

American (AMR) AF: 0.194 AC: 6845 AN: 35196

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 4261 AN: 22242

East Asian (EAS) AF: 0.162 AC: 5520 AN: 34018

South Asian (SAS) AF: 0.210 AC: 14708 AN: 69948

European-Finnish (FIN) AF: 0.221 AC: 10816 AN: 49000

Middle Eastern (MID) AF: 0.189 AC: 685 AN: 3620

European-Non Finnish (NFE) AF: 0.221 AC: 149108 AN: 675588

Other (OTH) AF: 0.196 AC: 8445 AN: 43144

GnomAD4 genome AF: 0.162 AC: 24642 AN: 152200 Hom.: 2419 Cov.: 32 AF XY: 0.161 AC XY: 12009 AN XY: 74412

African (AFR) AF: 0.0464 AC: 1927 AN: 41552

American (AMR) AF: 0.174 AC: 2654 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 636 AN: 3470

East Asian (EAS) AF: 0.180 AC: 936 AN: 5190

South Asian (SAS) AF: 0.198 AC: 956 AN: 4822

European-Finnish (FIN) AF: 0.217 AC: 2299 AN: 10580

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.214 AC: 14549 AN: 67982

Other (OTH) AF: 0.163 AC: 345 AN: 2112

Alfa AF: 0.196 Hom.: 3836

Bravo AF: 0.156

Asia WGS AF: 0.199 AC: 693 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.18
DANN	Benign	0.80
PhyloP100		-0.70
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

Other links and lift over

dbSNP: rs4986593; hg19: chr5-142693846;