rs190488

Variant names:

• chr5-143290743-T-G
• rs190488
• NM_000176.3:c.2023+4717A>C

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+4717A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.279 in 151,756 control chromosomes in the GnomAD database, including 6,153 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 0.28 (6153 hom., cov: 31)
• Consequence: NR3C1 NM_000176.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.697
• 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

ENSG00000300303 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• 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+4717A>C		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+4717A>C		intron_variant	Intron 7 of 8	1	NM_000176.3	ENSP00000377977.2

Frequencies

GnomAD3 genomes AF: 0.279 AC: 42277 AN: 151638 Hom.: 6154 Cov.: 31

Gnomad AFR AF: 0.268

Gnomad AMI AF: 0.332

Gnomad AMR AF: 0.199

Gnomad ASJ AF: 0.298

Gnomad EAS AF: 0.0733

Gnomad SAS AF: 0.190

Gnomad FIN AF: 0.279

Gnomad MID AF: 0.327

Gnomad NFE AF: 0.323

Gnomad OTH AF: 0.273

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

GnomAD4 genome AF: 0.279 AC: 42308 AN: 151756 Hom.: 6153 Cov.: 31 AF XY: 0.273 AC XY: 20220 AN XY: 74108

African (AFR) AF: 0.269 AC: 11126 AN: 41382

American (AMR) AF: 0.198 AC: 3012 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 1034 AN: 3466

East Asian (EAS) AF: 0.0732 AC: 377 AN: 5148

South Asian (SAS) AF: 0.190 AC: 909 AN: 4796

European-Finnish (FIN) AF: 0.279 AC: 2939 AN: 10536

Middle Eastern (MID) AF: 0.324 AC: 94 AN: 290

European-Non Finnish (NFE) AF: 0.323 AC: 21946 AN: 67928

Other (OTH) AF: 0.270 AC: 569 AN: 2108

Alfa AF: 0.304 Hom.: 891

Bravo AF: 0.271

Asia WGS AF: 0.153 AC: 533 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.9
DANN	Benign	0.72
PhyloP100		0.70
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: rs190488; hg19: chr5-142670308;