rs61753484

Variant names:

• chr5-143310259-C-G
• rs61753484
• NM_000176.3:c.1352-46G>C

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.1352-46G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00769 in 1,324,634 control chromosomes in the GnomAD database, including 53 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 0.0063 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0079 (49 hom.)
• Consequence: NR3C1 NM_000176.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.567
• Publications: 0 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=-0.87).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00628 (956/152254) while in subpopulation NFE AF = 0.00891 (606/68012). AF 95% confidence interval is 0.00832. There are 4 homozygotes in GnomAd4. There are 502 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 956 AD gene.

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.1352-46G>C		intron	N/A	NP_000167.1
	NR3C1	NM_001024094.2		c.1355-46G>C		intron	N/A	NP_001019265.1
	NR3C1	NM_001364183.2		c.1355-46G>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.1352-46G>C		intron	N/A	ENSP00000377977.2
	NR3C1	ENST00000231509.7	TSL:1	c.1355-46G>C		intron	N/A	ENSP00000231509.3
	NR3C1	ENST00000504572.5	TSL:1	c.1355-46G>C		intron	N/A	ENSP00000422518.1

Frequencies

GnomAD3 genomes AF: 0.00629 AC: 957 AN: 152136 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00167

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.0192

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00891

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00643 AC: 1555 AN: 241952 AF XY: 0.00664

Gnomad AFR exome AF: 0.00171

Gnomad AMR exome AF: 0.00193

Gnomad ASJ exome AF: 0.00172

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0207

Gnomad NFE exome AF: 0.00895

Gnomad OTH exome AF: 0.00401

GnomAD4 exome AF: 0.00787 AC: 9231 AN: 1172380 Hom.: 49 Cov.: 15 AF XY: 0.00782 AC XY: 4669 AN XY: 596974

African (AFR) AF: 0.00136 AC: 38 AN: 27940

American (AMR) AF: 0.00188 AC: 83 AN: 44154

Ashkenazi Jewish (ASJ) AF: 0.00161 AC: 39 AN: 24260

East Asian (EAS) AF: 0.00 AC: 0 AN: 38234

South Asian (SAS) AF: 0.00234 AC: 187 AN: 79774

European-Finnish (FIN) AF: 0.0184 AC: 879 AN: 47682

Middle Eastern (MID) AF: 0.000916 AC: 4 AN: 4368

European-Non Finnish (NFE) AF: 0.00900 AC: 7700 AN: 855236

Other (OTH) AF: 0.00593 AC: 301 AN: 50732

GnomAD4 genome AF: 0.00628 AC: 956 AN: 152254 Hom.: 4 Cov.: 32 AF XY: 0.00674 AC XY: 502 AN XY: 74444

African (AFR) AF: 0.00166 AC: 69 AN: 41552

American (AMR) AF: 0.00275 AC: 42 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4822

European-Finnish (FIN) AF: 0.0192 AC: 204 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00891 AC: 606 AN: 68012

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00595 Hom.: 1

Bravo AF: 0.00459

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.45
DANN	Benign	0.35
PhyloP100		-0.57
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: rs61753484; hg19: chr5-142689824;