5-143293832-A-G

Variant names:

• chr5-143293832-A-G
• rs17209258
• NM_000176.3:c.2023+1628T>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+1628T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 926,686 control chromosomes in the GnomAD database, including 18,718 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 0.16 (2398 hom., cov: 31)
  • Exomes 𝑓: 0.20 (16320 hom.)
• Consequence: NR3C1 NM_000176.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.399
• Publications: 17 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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.21 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C1	NM_000176.3	MANE Select	c.2023+1628T>C		intron	N/A	NP_000167.1
	NR3C1	NM_001024094.2		c.2026+1628T>C		intron	N/A	NP_001019265.1
	NR3C1	NM_001364183.2		c.2026+1628T>C		intron	N/A	NP_001351112.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C1	ENST00000394464.7	TSL:1 MANE Select	c.2023+1628T>C		intron	N/A	ENSP00000377977.2
	NR3C1	ENST00000231509.7	TSL:1	c.2026+1628T>C		intron	N/A	ENSP00000231509.3
	NR3C1	ENST00000504572.5	TSL:1	c.2026+1628T>C		intron	N/A	ENSP00000422518.1

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24513 AN: 151480 Hom.: 2397 Cov.: 31

Gnomad AFR AF: 0.0470

Gnomad AMI AF: 0.284

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.182

Gnomad EAS AF: 0.181

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.219

Gnomad MID AF: 0.245

Gnomad NFE AF: 0.213

Gnomad OTH AF: 0.162

GnomAD4 exome AF: 0.202 AC: 156921 AN: 775104 Hom.: 16320 Cov.: 12 AF XY: 0.203 AC XY: 72836 AN XY: 359266

African (AFR) AF: 0.0304 AC: 448 AN: 14740

American (AMR) AF: 0.176 AC: 158 AN: 900

Ashkenazi Jewish (ASJ) AF: 0.182 AC: 879 AN: 4836

East Asian (EAS) AF: 0.170 AC: 571 AN: 3364

South Asian (SAS) AF: 0.195 AC: 2974 AN: 15256

European-Finnish (FIN) AF: 0.202 AC: 53 AN: 262

Middle Eastern (MID) AF: 0.188 AC: 286 AN: 1522

European-Non Finnish (NFE) AF: 0.207 AC: 146729 AN: 708816

Other (OTH) AF: 0.190 AC: 4823 AN: 25408

GnomAD4 genome AF: 0.162 AC: 24515 AN: 151582 Hom.: 2398 Cov.: 31 AF XY: 0.162 AC XY: 11973 AN XY: 74056

African (AFR) AF: 0.0469 AC: 1942 AN: 41426

American (AMR) AF: 0.175 AC: 2658 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.182 AC: 631 AN: 3468

East Asian (EAS) AF: 0.180 AC: 932 AN: 5166

South Asian (SAS) AF: 0.195 AC: 936 AN: 4798

European-Finnish (FIN) AF: 0.219 AC: 2269 AN: 10370

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.213 AC: 14468 AN: 67830

Other (OTH) AF: 0.164 AC: 344 AN: 2100

Alfa AF: 0.195 Hom.: 3827

Bravo AF: 0.156

Asia WGS AF: 0.195 AC: 678 AN: 3464

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.87
DANN	Benign	0.72
PhyloP100		-0.40
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: rs17209258; hg19: chr5-142673397; COSMIC: COSV51541189;