rs852979

Variant names:

• chr5-143313833-T-C
• rs852979
• NM_000176.3:c.1351+169A>G

Variant summary

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

The NM_000176.3(NR3C1):​c.1351+169A>G 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 152,110 control chromosomes in the GnomAD database, including 6,189 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 (6189 hom., cov: 31)
• Consequence: NR3C1 NM_000176.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.32
• Publications: 6 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=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.32 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR3C1	NM_000176.3	c.1351+169A>G		intron_variant	Intron 3 of 8	ENST00000394464.7	NP_000167.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR3C1	ENST00000394464.7	c.1351+169A>G		intron_variant	Intron 3 of 8	1	NM_000176.3	ENSP00000377977.2

Frequencies

GnomAD3 genomes AF: 0.279 AC: 42451 AN: 151992 Hom.: 6190 Cov.: 31

Gnomad AFR AF: 0.268

Gnomad AMI AF: 0.332

Gnomad AMR AF: 0.198

Gnomad ASJ AF: 0.301

Gnomad EAS AF: 0.0754

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.283

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.324

Gnomad OTH AF: 0.272

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

GnomAD4 genome AF: 0.279 AC: 42483 AN: 152110 Hom.: 6189 Cov.: 31 AF XY: 0.274 AC XY: 20337 AN XY: 74342

African (AFR) AF: 0.269 AC: 11147 AN: 41494

American (AMR) AF: 0.198 AC: 3022 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.301 AC: 1043 AN: 3470

East Asian (EAS) AF: 0.0754 AC: 391 AN: 5186

South Asian (SAS) AF: 0.192 AC: 924 AN: 4820

European-Finnish (FIN) AF: 0.283 AC: 2992 AN: 10566

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.324 AC: 21998 AN: 67974

Other (OTH) AF: 0.270 AC: 570 AN: 2114

Alfa AF: 0.304 Hom.: 892

Bravo AF: 0.272

Asia WGS AF: 0.154 AC: 536 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.2
DANN	Benign	0.78
PhyloP100		-1.3
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: rs852979; hg19: chr5-142693398;