5-143296616-AAACAAC-AAAC

Variant names:

• chr5-143296616-AAAC-A
• rs2307674
• NM_000176.3:c.1893-1029_1893-1027delGTT

Variant summary

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

The NM_000176.3(NR3C1):​c.1893-1029_1893-1027delGTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 152,060 control chromosomes in the GnomAD database, including 1,759 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.14 (1759 hom., cov: 28)
• Consequence: NR3C1 NM_000176.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.430
• Publications: 1 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.162 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.1893-1029_1893-1027delGTT		intron	N/A	NP_000167.1	P04150-1
	NR3C1	NM_001024094.2		c.1896-1029_1896-1027delGTT		intron	N/A	NP_001019265.1	E5KQF6
	NR3C1	NM_001364183.2		c.1896-1029_1896-1027delGTT		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.1893-1029_1893-1027delGTT		intron	N/A	ENSP00000377977.2	P04150-1
	NR3C1	ENST00000231509.7	TSL:1	c.1896-1029_1896-1027delGTT		intron	N/A	ENSP00000231509.3	P04150-3
	NR3C1	ENST00000504572.5	TSL:1	c.1896-1029_1896-1027delGTT		intron	N/A	ENSP00000422518.1	P04150-3

Frequencies

GnomAD3 genomes AF: 0.145 AC: 21990 AN: 151944 Hom.: 1755 Cov.: 28

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.240

Gnomad AMR AF: 0.0812

Gnomad ASJ AF: 0.0622

Gnomad EAS AF: 0.0710

Gnomad SAS AF: 0.0334

Gnomad FIN AF: 0.201

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.117

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

GnomAD4 genome AF: 0.145 AC: 22018 AN: 152060 Hom.: 1759 Cov.: 28 AF XY: 0.143 AC XY: 10619 AN XY: 74332

African (AFR) AF: 0.165 AC: 6858 AN: 41468

American (AMR) AF: 0.0811 AC: 1240 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0622 AC: 216 AN: 3472

East Asian (EAS) AF: 0.0709 AC: 367 AN: 5174

South Asian (SAS) AF: 0.0324 AC: 156 AN: 4818

European-Finnish (FIN) AF: 0.201 AC: 2123 AN: 10546

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.156 AC: 10589 AN: 67980

Other (OTH) AF: 0.116 AC: 245 AN: 2106

Alfa AF: 0.0561 Hom.: 63

Bravo AF: 0.137

Asia WGS AF: 0.0720 AC: 250 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.43
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: rs2307674; hg19: chr5-142676181;