chr5-143427467-G-A

Variant names:

• chr5-143427467-G-A
• rs4912911
• ENST00000504572.5:c.-14+6252C>T

Variant summary

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

The ENST00000504572.5(NR3C1):​c.-14+6252C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.564 in 151,614 control chromosomes in the GnomAD database, including 25,381 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 0.56 (25381 hom., cov: 30)
• Consequence: NR3C1 ENST00000504572.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.473
• 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: 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=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.66 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR3C1	NM_001364183.2	c.-14+6252C>T		intron_variant	Intron 2 of 9		NP_001351112.1
NR3C1	NM_001018074.1	c.-14+7737C>T		intron_variant	Intron 1 of 8		NP_001018084.1
NR3C1	NM_001018075.1	c.-14+7834C>T		intron_variant	Intron 1 of 8		NP_001018085.1
NR3C1	NM_001018077.1	c.-14+7065C>T		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+6252C>T		intron_variant	Intron 2 of 9	1		ENSP00000422518.1
NR3C1	ENST00000343796.6	c.-14+7065C>T		intron_variant	Intron 1 of 8	5		ENSP00000343205.2
NR3C1	ENST00000503701.1	n.352+6252C>T		intron_variant	Intron 2 of 2	3
NR3C1	ENST00000505058.5	n.241+7065C>T		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.564 AC: 85460 AN: 151494 Hom.: 25385 Cov.: 30

Gnomad AFR AF: 0.360

Gnomad AMI AF: 0.632

Gnomad AMR AF: 0.574

Gnomad ASJ AF: 0.730

Gnomad EAS AF: 0.561

Gnomad SAS AF: 0.577

Gnomad FIN AF: 0.628

Gnomad MID AF: 0.615

Gnomad NFE AF: 0.665

Gnomad OTH AF: 0.584

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

GnomAD4 genome AF: 0.564 AC: 85480 AN: 151614 Hom.: 25381 Cov.: 30 AF XY: 0.563 AC XY: 41681 AN XY: 74022

African (AFR) AF: 0.359 AC: 14835 AN: 41278

American (AMR) AF: 0.573 AC: 8731 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.730 AC: 2533 AN: 3470

East Asian (EAS) AF: 0.561 AC: 2879 AN: 5136

South Asian (SAS) AF: 0.577 AC: 2766 AN: 4794

European-Finnish (FIN) AF: 0.628 AC: 6580 AN: 10486

Middle Eastern (MID) AF: 0.600 AC: 174 AN: 290

European-Non Finnish (NFE) AF: 0.665 AC: 45168 AN: 67910

Other (OTH) AF: 0.587 AC: 1238 AN: 2110

Alfa AF: 0.629 Hom.: 16311

Bravo AF: 0.549

Asia WGS AF: 0.544 AC: 1894 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.4
DANN	Benign	0.20
PhyloP100		0.47
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: rs4912911; hg19: chr5-142807032; COSMIC: COSV59429833;