rs10482606

Variant names:

• chr5-143403703-A-G
• rs10482606
• ENST00000504572.5:c.-13-2851T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001364183.2(NR3C1):​c.-13-2851T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.005 in 983,372 control chromosomes in the GnomAD database, including 11 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 0.0038 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0052 (9 hom.)
• Consequence: NR3C1 NM_001364183.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.641
• Publications: 3 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)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00377 (567/150546) while in subpopulation NFE AF = 0.0056 (380/67822). AF 95% confidence interval is 0.00514. There are 2 homozygotes in GnomAd4. There are 270 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 567 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001364183.2. 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_001364183.2		c.-13-2851T>C		intron	N/A	NP_001351112.1	P04150-3
	NR3C1	NM_001364184.2		c.-14+673T>C		intron	N/A	NP_001351113.1	E5KQF6
	NR3C1	NM_001018074.1		c.-13-2851T>C		intron	N/A	NP_001018084.1	P04150-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C1	ENST00000504572.5	TSL:1	c.-13-2851T>C		intron	N/A	ENSP00000422518.1	P04150-3
	NR3C1	ENST00000503201.1	TSL:1	c.-14+673T>C		intron	N/A	ENSP00000427672.1	P04150-1
	NR3C1	ENST00000502892.5	TSL:1	c.-14+916T>C		intron	N/A	ENSP00000420856.1	Q3MSN4

Frequencies

GnomAD3 genomes AF: 0.00377 AC: 567 AN: 150442 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00122

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.000578

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00560

Gnomad OTH AF: 0.00193

GnomAD4 exome AF: 0.00522 AC: 4349 AN: 832826 Hom.: 9 Cov.: 32 AF XY: 0.00530 AC XY: 2040 AN XY: 384650

African (AFR) AF: 0.000587 AC: 9 AN: 15336

American (AMR) AF: 0.00203 AC: 2 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.000388 AC: 2 AN: 5158

East Asian (EAS) AF: 0.00 AC: 0 AN: 3638

South Asian (SAS) AF: 0.0000607 AC: 1 AN: 16466

European-Finnish (FIN) AF: 0.0107 AC: 3 AN: 280

Middle Eastern (MID) AF: 0.000617 AC: 1 AN: 1620

European-Non Finnish (NFE) AF: 0.00557 AC: 4248 AN: 762090

Other (OTH) AF: 0.00305 AC: 83 AN: 27254

GnomAD4 genome AF: 0.00377 AC: 567 AN: 150546 Hom.: 2 Cov.: 33 AF XY: 0.00367 AC XY: 270 AN XY: 73622

African (AFR) AF: 0.00122 AC: 49 AN: 40256

American (AMR) AF: 0.00105 AC: 16 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.000578 AC: 2 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.0106 AC: 111 AN: 10482

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00560 AC: 380 AN: 67822

Other (OTH) AF: 0.00191 AC: 4 AN: 2096

Alfa AF: 0.00427 Hom.: 0

Bravo AF: 0.00297

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	16
DANN	Benign	0.43
PhyloP100		0.64
PromoterAI		0.087	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10482606; hg19: chr5-142783268;