rs10515522

Variant names:

• chr5-143378829-T-C
• rs10515522
• NM_000176.3:c.1184+20827A>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+20827A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 152,244 control chromosomes in the GnomAD database, including 1,133 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 0.11 (1133 hom., cov: 32)
• Consequence: NR3C1 NM_000176.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.521
• Publications: 12 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: Orphanet, Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.153 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000176.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C1	NM_000176.3	MANE Select	c.1184+20827A>G		intron	N/A	NP_000167.1	P04150-1
	NR3C1	NM_001024094.2		c.1184+20827A>G		intron	N/A	NP_001019265.1	E5KQF6
	NR3C1	NM_001364183.2		c.1184+20827A>G		intron	N/A	NP_001351112.1	P04150-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C1	ENST00000394464.7	TSL:1 MANE Select	c.1184+20827A>G		intron	N/A	ENSP00000377977.2	P04150-1
	NR3C1	ENST00000231509.7	TSL:1	c.1184+20827A>G		intron	N/A	ENSP00000231509.3	P04150-3
	NR3C1	ENST00000504572.5	TSL:1	c.1184+20827A>G		intron	N/A	ENSP00000422518.1	P04150-3

Frequencies

GnomAD3 genomes AF: 0.105 AC: 15998 AN: 152126 Hom.: 1133 Cov.: 32

Gnomad AFR AF: 0.0404

Gnomad AMI AF: 0.240

Gnomad AMR AF: 0.0690

Gnomad ASJ AF: 0.0687

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0230

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.0933

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

GnomAD4 genome AF: 0.105 AC: 15999 AN: 152244 Hom.: 1133 Cov.: 32 AF XY: 0.103 AC XY: 7677 AN XY: 74452

African (AFR) AF: 0.0404 AC: 1679 AN: 41558

American (AMR) AF: 0.0690 AC: 1055 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0687 AC: 238 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.0224 AC: 108 AN: 4830

European-Finnish (FIN) AF: 0.183 AC: 1937 AN: 10598

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.155 AC: 10565 AN: 67988

Other (OTH) AF: 0.0923 AC: 195 AN: 2112

Alfa AF: 0.129 Hom.: 1693

Bravo AF: 0.0945

Asia WGS AF: 0.0150 AC: 52 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.73
DANN	Benign	0.73
PhyloP100		-0.52
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: rs10515522; hg19: chr5-142758394;