rs12656106

Variant names:

• chr5-143429382-G-C
• rs12656106
• ENST00000504572.5:c.-14+4337C>G

Variant summary

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

The NM_001364183.2(NR3C1):​c.-14+4337C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 152,164 control chromosomes in the GnomAD database, including 11,358 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 0.37 (11358 hom., cov: 33)
• Consequence: NR3C1 NM_001364183.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.807
• Publications: 22 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001364183.2. 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_001364183.2		c.-14+4337C>G		intron	N/A	NP_001351112.1	P04150-3
	NR3C1	NM_001018074.1		c.-14+5822C>G		intron	N/A	NP_001018084.1	P04150-1
	NR3C1	NM_001018075.1		c.-14+5919C>G		intron	N/A	NP_001018085.1	P04150-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C1	ENST00000504572.5	TSL:1	c.-14+4337C>G		intron	N/A	ENSP00000422518.1	P04150-3
	NR3C1	ENST00000870492.1		c.-14+5150C>G		intron	N/A	ENSP00000540551.1
	NR3C1	ENST00000343796.6	TSL:5	c.-14+5150C>G		intron	N/A	ENSP00000343205.2	P04150-1

Frequencies

GnomAD3 genomes AF: 0.367 AC: 55838 AN: 152046 Hom.: 11361 Cov.: 33

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.453

Gnomad AMR AF: 0.406

Gnomad ASJ AF: 0.449

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.408

Gnomad FIN AF: 0.426

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.382

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

GnomAD4 genome AF: 0.367 AC: 55838 AN: 152164 Hom.: 11358 Cov.: 33 AF XY: 0.367 AC XY: 27279 AN XY: 74390

African (AFR) AF: 0.174 AC: 7205 AN: 41522

American (AMR) AF: 0.406 AC: 6204 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.449 AC: 1558 AN: 3472

East Asian (EAS) AF: 0.432 AC: 2233 AN: 5172

South Asian (SAS) AF: 0.409 AC: 1970 AN: 4822

European-Finnish (FIN) AF: 0.426 AC: 4506 AN: 10580

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.453 AC: 30816 AN: 67994

Other (OTH) AF: 0.380 AC: 802 AN: 2112

Alfa AF: 0.404 Hom.: 1650

Bravo AF: 0.358

Asia WGS AF: 0.349 AC: 1218 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.37
DANN	Benign	0.48
PhyloP100		-0.81
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12656106; hg19: chr5-142808947; COSMIC: COSV59429848;