5-143404384-C-CG

Variant names:

• chr5-143404384-C-CG
• rs5871845
• ENST00000503201.1:c.-23dupC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The ENST00000503201.1(NR3C1):​c.-23dupC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0596 in 985,276 control chromosomes in the GnomAD database, including 2,059 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.063 (444 hom., cov: 31)
  • Exomes 𝑓: 0.059 (1615 hom.)
• Consequence: NR3C1 ENST00000503201.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.140
• Publications: 9 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR3C1	NR_157096.2	n.98dupC		non_coding_transcript_exon_variant	Exon 1 of 8
NR3C1	NM_001364184.2	c.-23dupC		5_prime_UTR_variant	Exon 1 of 9		NP_001351113.1
NR3C1	NM_001018076.2	c.-23dupC		5_prime_UTR_variant	Exon 1 of 9		NP_001018086.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR3C1	ENST00000503201.1	c.-23dupC		5_prime_UTR_variant	Exon 1 of 9	1		ENSP00000427672.1
NR3C1	ENST00000504572.5	c.-13-3533dupC		intron_variant	Intron 2 of 9	1		ENSP00000422518.1
NR3C1	ENST00000502892.5	c.-14+234dupC		intron_variant	Intron 1 of 1	1		ENSP00000420856.1

Frequencies

GnomAD3 genomes AF: 0.0633 AC: 9619 AN: 151946 Hom.: 442 Cov.: 31

Gnomad AFR AF: 0.0544

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0540

Gnomad ASJ AF: 0.0329

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.0455

Gnomad MID AF: 0.105

Gnomad NFE AF: 0.0559

Gnomad OTH AF: 0.0632

GnomAD4 exome AF: 0.0589 AC: 49050 AN: 833220 Hom.: 1615 Cov.: 32 AF XY: 0.0585 AC XY: 22504 AN XY: 384810

African (AFR) AF: 0.0564 AC: 890 AN: 15788

American (AMR) AF: 0.0447 AC: 44 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.0345 AC: 178 AN: 5154

East Asian (EAS) AF: 0.240 AC: 872 AN: 3632

South Asian (SAS) AF: 0.146 AC: 2398 AN: 16462

European-Finnish (FIN) AF: 0.0399 AC: 11 AN: 276

Middle Eastern (MID) AF: 0.0790 AC: 128 AN: 1620

European-Non Finnish (NFE) AF: 0.0559 AC: 42572 AN: 762002

Other (OTH) AF: 0.0717 AC: 1957 AN: 27302

GnomAD4 genome AF: 0.0633 AC: 9627 AN: 152056 Hom.: 444 Cov.: 31 AF XY: 0.0652 AC XY: 4844 AN XY: 74346

African (AFR) AF: 0.0543 AC: 2255 AN: 41506

American (AMR) AF: 0.0539 AC: 824 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0329 AC: 114 AN: 3468

East Asian (EAS) AF: 0.229 AC: 1175 AN: 5134

South Asian (SAS) AF: 0.162 AC: 779 AN: 4810

European-Finnish (FIN) AF: 0.0455 AC: 482 AN: 10588

Middle Eastern (MID) AF: 0.110 AC: 32 AN: 292

European-Non Finnish (NFE) AF: 0.0559 AC: 3798 AN: 67948

Other (OTH) AF: 0.0634 AC: 134 AN: 2112

Alfa AF: 0.0134 Hom.: 6

Bravo AF: 0.0602

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.14
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: rs5871845; hg19: chr5-142783949;