rs10482604

Variant names:

• chr5-143404037-T-C
• rs10482604
• ENST00000504572.5:c.-13-3185A>G

Variant summary

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

The NM_001364181.2(NR3C1):​c.-65A>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 0.00134 in 985,386 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 0.0054 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (6 hom.)
• Consequence: NR3C1 NM_001364181.2 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.309
• Publications: 4 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=-0.77).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00536 (814/151918) while in subpopulation EAS AF = 0.0223 (114/5120). AF 95% confidence interval is 0.0189. There are 5 homozygotes in GnomAd4. There are 409 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 814 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001364181.2. 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_001364181.2		c.-65A>G		5_prime_UTR	Exon 1 of 9	NP_001351110.1
	NR3C1	NM_001364183.2		c.-13-3185A>G		intron	N/A	NP_001351112.1
	NR3C1	NM_001364184.2		c.-14+339A>G		intron	N/A	NP_001351113.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C1	ENST00000504572.5	TSL:1	c.-13-3185A>G		intron	N/A	ENSP00000422518.1
	NR3C1	ENST00000503201.1	TSL:1	c.-14+339A>G		intron	N/A	ENSP00000427672.1
	NR3C1	ENST00000502892.5	TSL:1	c.-14+582A>G		intron	N/A	ENSP00000420856.1

Frequencies

GnomAD3 genomes AF: 0.00531 AC: 806 AN: 151810 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0151

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0222

Gnomad SAS AF: 0.00434

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000133

Gnomad OTH AF: 0.00478

GnomAD4 exome AF: 0.000605 AC: 504 AN: 833468 Hom.: 6 Cov.: 32 AF XY: 0.000561 AC XY: 216 AN XY: 384974

African (AFR) AF: 0.0151 AC: 239 AN: 15792

American (AMR) AF: 0.00101 AC: 1 AN: 986

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5154

East Asian (EAS) AF: 0.0297 AC: 108 AN: 3636

South Asian (SAS) AF: 0.00133 AC: 22 AN: 16514

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 282

Middle Eastern (MID) AF: 0.00185 AC: 3 AN: 1620

European-Non Finnish (NFE) AF: 0.0000446 AC: 34 AN: 762168

Other (OTH) AF: 0.00355 AC: 97 AN: 27316

GnomAD4 genome AF: 0.00536 AC: 814 AN: 151918 Hom.: 5 Cov.: 32 AF XY: 0.00551 AC XY: 409 AN XY: 74248

African (AFR) AF: 0.0152 AC: 629 AN: 41454

American (AMR) AF: 0.00183 AC: 28 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.0223 AC: 114 AN: 5120

South Asian (SAS) AF: 0.00414 AC: 20 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10552

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

European-Non Finnish (NFE) AF: 0.000133 AC: 9 AN: 67904

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.00156 Hom.: 1

Bravo AF: 0.00569

Asia WGS AF: 0.0170 AC: 58 AN: 3462

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	11
DANN	Benign	0.68
PhyloP100		0.31
PromoterAI		0.082	Neutral

Splicing

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

Other links and lift over

dbSNP: rs10482604; hg19: chr5-142783602;