rs258813

Variant names:

• chr5-143295125-G-A
• rs258813
• NM_000176.3:c.2023+335C>T

Variant summary

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

The NM_000176.3(NR3C1):​c.2023+335C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.317 in 984,728 control chromosomes in the GnomAD database, including 49,905 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 0.29 (6528 hom., cov: 32)
  • Exomes 𝑓: 0.32 (43377 hom.)
• Consequence: NR3C1 NM_000176.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.741
• Publications: 15 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

ENSG00000300303 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR3C1	NM_000176.3	c.2023+335C>T		intron_variant	Intron 7 of 8	ENST00000394464.7	NP_000167.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR3C1	ENST00000394464.7	c.2023+335C>T		intron_variant	Intron 7 of 8	1	NM_000176.3	ENSP00000377977.2

Frequencies

GnomAD3 genomes AF: 0.287 AC: 43603 AN: 151820 Hom.: 6521 Cov.: 32

Gnomad AFR AF: 0.297

Gnomad AMI AF: 0.331

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.294

Gnomad EAS AF: 0.0959

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.280

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.322

Gnomad OTH AF: 0.280

GnomAD4 exome AF: 0.322 AC: 268155 AN: 832788 Hom.: 43377 Cov.: 31 AF XY: 0.322 AC XY: 123884 AN XY: 384568

African (AFR) AF: 0.303 AC: 4789 AN: 15780

American (AMR) AF: 0.203 AC: 200 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 1496 AN: 5144

East Asian (EAS) AF: 0.113 AC: 411 AN: 3630

South Asian (SAS) AF: 0.202 AC: 3321 AN: 16460

European-Finnish (FIN) AF: 0.319 AC: 88 AN: 276

Middle Eastern (MID) AF: 0.303 AC: 491 AN: 1620

European-Non Finnish (NFE) AF: 0.327 AC: 249057 AN: 761618

Other (OTH) AF: 0.304 AC: 8302 AN: 27276

GnomAD4 genome AF: 0.287 AC: 43646 AN: 151940 Hom.: 6528 Cov.: 32 AF XY: 0.281 AC XY: 20878 AN XY: 74244

African (AFR) AF: 0.298 AC: 12328 AN: 41400

American (AMR) AF: 0.200 AC: 3048 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 1018 AN: 3466

East Asian (EAS) AF: 0.0959 AC: 496 AN: 5172

South Asian (SAS) AF: 0.194 AC: 935 AN: 4820

European-Finnish (FIN) AF: 0.280 AC: 2948 AN: 10540

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.322 AC: 21889 AN: 67944

Other (OTH) AF: 0.279 AC: 590 AN: 2114

Alfa AF: 0.305 Hom.: 18931

Bravo AF: 0.281

Asia WGS AF: 0.171 AC: 596 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.9
DANN	Benign	0.10
PhyloP100		0.74
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: rs258813; hg19: chr5-142674690; COSMIC: COSV51545682;