5-143429707-T-C

Variant names:

• chr5-143429707-T-C
• rs12655166
• ENST00000504572.5:c.-14+4012A>G

Variant summary

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

The ENST00000504572.5(NR3C1):​c.-14+4012A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 152,144 control chromosomes in the GnomAD database, including 3,678 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 0.20 (3678 hom., cov: 32)
• Consequence: NR3C1 ENST00000504572.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.798
• Publications: 19 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.26 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR3C1	NM_001364183.2	c.-14+4012A>G		intron_variant	Intron 2 of 9		NP_001351112.1
NR3C1	NM_001018074.1	c.-14+5497A>G		intron_variant	Intron 1 of 8		NP_001018084.1
NR3C1	NM_001018075.1	c.-14+5594A>G		intron_variant	Intron 1 of 8		NP_001018085.1
NR3C1	NM_001018077.1	c.-14+4825A>G		intron_variant	Intron 1 of 8		NP_001018087.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR3C1	ENST00000504572.5	c.-14+4012A>G		intron_variant	Intron 2 of 9	1		ENSP00000422518.1
NR3C1	ENST00000343796.6	c.-14+4825A>G		intron_variant	Intron 1 of 8	5		ENSP00000343205.2
NR3C1	ENST00000503701.1	n.352+4012A>G		intron_variant	Intron 2 of 2	3
NR3C1	ENST00000505058.5	n.241+4825A>G		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29726 AN: 152026 Hom.: 3672 Cov.: 32

Gnomad AFR AF: 0.0482

Gnomad AMI AF: 0.257

Gnomad AMR AF: 0.264

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.270

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.195

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

GnomAD4 genome AF: 0.195 AC: 29737 AN: 152144 Hom.: 3678 Cov.: 32 AF XY: 0.197 AC XY: 14679 AN XY: 74374

African (AFR) AF: 0.0482 AC: 2001 AN: 41510

American (AMR) AF: 0.264 AC: 4041 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 468 AN: 3472

East Asian (EAS) AF: 0.122 AC: 634 AN: 5190

South Asian (SAS) AF: 0.245 AC: 1179 AN: 4818

European-Finnish (FIN) AF: 0.270 AC: 2850 AN: 10568

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.263 AC: 17872 AN: 67986

Other (OTH) AF: 0.193 AC: 407 AN: 2114

Alfa AF: 0.241 Hom.: 5302

Bravo AF: 0.189

Asia WGS AF: 0.200 AC: 696 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	0.054
DANN	Benign	0.73
PhyloP100		-0.80
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: rs12655166; hg19: chr5-142809272;