NM_000176.3:c.1468+2168T>C

Variant names:

• chr5-143307929-A-G
• rs852977
• NM_000176.3:c.1468+2168T>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.1468+2168T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.289 in 152,100 control chromosomes in the GnomAD database, including 6,632 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 (6632 hom., cov: 31)
• Consequence: NR3C1 NM_000176.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.113
• Publications: 23 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: Orphanet, Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000300303 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000176.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C1	NM_000176.3	MANE Select	c.1468+2168T>C		intron	N/A	NP_000167.1	P04150-1
	NR3C1	NM_001024094.2		c.1471+2168T>C		intron	N/A	NP_001019265.1	E5KQF6
	NR3C1	NM_001364183.2		c.1471+2168T>C		intron	N/A	NP_001351112.1	P04150-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C1	ENST00000394464.7	TSL:1 MANE Select	c.1468+2168T>C		intron	N/A	ENSP00000377977.2	P04150-1
	NR3C1	ENST00000231509.7	TSL:1	c.1471+2168T>C		intron	N/A	ENSP00000231509.3	P04150-3
	NR3C1	ENST00000504572.5	TSL:1	c.1471+2168T>C		intron	N/A	ENSP00000422518.1	P04150-3

Frequencies

GnomAD3 genomes AF: 0.289 AC: 43986 AN: 151982 Hom.: 6624 Cov.: 31

Gnomad AFR AF: 0.299

Gnomad AMI AF: 0.331

Gnomad AMR AF: 0.201

Gnomad ASJ AF: 0.300

Gnomad EAS AF: 0.0964

Gnomad SAS AF: 0.197

Gnomad FIN AF: 0.283

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.324

Gnomad OTH AF: 0.283

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

GnomAD4 genome AF: 0.289 AC: 44032 AN: 152100 Hom.: 6632 Cov.: 31 AF XY: 0.284 AC XY: 21101 AN XY: 74364

African (AFR) AF: 0.300 AC: 12440 AN: 41468

American (AMR) AF: 0.201 AC: 3074 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.300 AC: 1043 AN: 3472

East Asian (EAS) AF: 0.0964 AC: 500 AN: 5186

South Asian (SAS) AF: 0.196 AC: 945 AN: 4824

European-Finnish (FIN) AF: 0.283 AC: 2995 AN: 10570

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.324 AC: 22043 AN: 67972

Other (OTH) AF: 0.282 AC: 595 AN: 2112

Alfa AF: 0.304 Hom.: 20501

Bravo AF: 0.283

Asia WGS AF: 0.171 AC: 594 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	4.9
DANN	Benign	0.46
PhyloP100		0.11
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: rs852977; hg19: chr5-142687494;