rs10482609

Variant names:

• chr5-143403522-A-C
• rs10482609
• NM_000176.3:c.-325T>G

Variant summary

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

The NM_000176.3(NR3C1):​c.-325T>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00846 in 985,064 control chromosomes in the GnomAD database, including 74 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 0.010 (21 hom., cov: 33)
  • Exomes 𝑓: 0.0081 (53 hom.)
• Consequence: NR3C1 NM_000176.3 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.328
• Publications: 2 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=-0.51).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0104 (1575/151716) while in subpopulation SAS AF = 0.0363 (175/4820). AF 95% confidence interval is 0.0319. There are 21 homozygotes in GnomAd4. There are 832 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1575 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR3C1	NM_000176.3	c.-325T>G		5_prime_UTR_variant	Exon 1 of 9	ENST00000394464.7	NP_000167.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR3C1	ENST00000394464.7	c.-325T>G		5_prime_UTR_variant	Exon 1 of 9	1	NM_000176.3	ENSP00000377977.2

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1572 AN: 151608 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.00146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.0649

Gnomad EAS AF: 0.0220

Gnomad SAS AF: 0.0361

Gnomad FIN AF: 0.0128

Gnomad MID AF: 0.0258

Gnomad NFE AF: 0.00854

Gnomad OTH AF: 0.0177

GnomAD4 exome AF: 0.00811 AC: 6758 AN: 833348 Hom.: 53 Cov.: 32 AF XY: 0.00843 AC XY: 3246 AN XY: 384892

African (AFR) AF: 0.00146 AC: 23 AN: 15792

American (AMR) AF: 0.00609 AC: 6 AN: 986

Ashkenazi Jewish (ASJ) AF: 0.0623 AC: 321 AN: 5154

East Asian (EAS) AF: 0.0253 AC: 92 AN: 3642

South Asian (SAS) AF: 0.0371 AC: 611 AN: 16466

European-Finnish (FIN) AF: 0.00694 AC: 2 AN: 288

Middle Eastern (MID) AF: 0.0370 AC: 60 AN: 1622

European-Non Finnish (NFE) AF: 0.00687 AC: 5236 AN: 762096

Other (OTH) AF: 0.0149 AC: 407 AN: 27302

GnomAD4 genome AF: 0.0104 AC: 1575 AN: 151716 Hom.: 21 Cov.: 33 AF XY: 0.0112 AC XY: 832 AN XY: 74142

African (AFR) AF: 0.00145 AC: 60 AN: 41354

American (AMR) AF: 0.0158 AC: 241 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0649 AC: 225 AN: 3466

East Asian (EAS) AF: 0.0221 AC: 112 AN: 5076

South Asian (SAS) AF: 0.0363 AC: 175 AN: 4820

European-Finnish (FIN) AF: 0.0128 AC: 135 AN: 10534

Middle Eastern (MID) AF: 0.0278 AC: 8 AN: 288

European-Non Finnish (NFE) AF: 0.00854 AC: 580 AN: 67876

Other (OTH) AF: 0.0185 AC: 39 AN: 2108

Alfa AF: 0.00873 Hom.: 1

Bravo AF: 0.00997

Asia WGS AF: 0.0450 AC: 155 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Benign	0.78
PhyloP100		0.33
PromoterAI		0.019	Neutral
Mutation Taster		=100/0	polymorphism

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: rs10482609; hg19: chr5-142783087; COSMIC: COSV51542047; COSMIC: COSV51542047;