5-143405048-C-T

Variant names:

• chr5-143405048-C-T
• rs10482603
• ENST00000504572.5:c.-13-4196G>A

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.-13-4196G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0084 in 868,340 control chromosomes in the GnomAD database, including 71 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: 31)
  • Exomes 𝑓: 0.0080 (50 hom.)
• Consequence: NR3C1 NM_001364183.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.230
• 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: Orphanet, Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae)

LOC128966704 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0104 (1577/152316) while in subpopulation SAS AF = 0.036 (174/4828). AF 95% confidence interval is 0.0317. There are 21 homozygotes in GnomAd4. There are 833 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1577 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.-13-4196G>A		intron	N/A	NP_001351112.1	P04150-3
	NR3C1	NM_001018074.1		c.-13-4196G>A		intron	N/A	NP_001018084.1	P04150-1
	NR3C1	NM_001018075.1		c.-13-4196G>A		intron	N/A	NP_001018085.1	P04150-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C1	ENST00000504572.5	TSL:1	c.-13-4196G>A		intron	N/A	ENSP00000422518.1	P04150-3
	NR3C1	ENST00000514699.1	TSL:1	c.-14+102G>A		intron	N/A	ENSP00000426478.1	Q3MSN4
	NR3C1	ENST00000870492.1		c.-13-4196G>A		intron	N/A	ENSP00000540551.1

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1573 AN: 152198 Hom.: 21 Cov.: 31

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0159

Gnomad ASJ AF: 0.0648

Gnomad EAS AF: 0.0216

Gnomad SAS AF: 0.0358

Gnomad FIN AF: 0.0127

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00851

Gnomad OTH AF: 0.0181

GnomAD4 exome AF: 0.00798 AC: 5713 AN: 716024 Hom.: 50 AF XY: 0.00827 AC XY: 2750 AN XY: 332618

African (AFR) AF: 0.00173 AC: 23 AN: 13276

American (AMR) AF: 0.00489 AC: 4 AN: 818

Ashkenazi Jewish (ASJ) AF: 0.0615 AC: 270 AN: 4388

East Asian (EAS) AF: 0.0254 AC: 78 AN: 3070

South Asian (SAS) AF: 0.0380 AC: 537 AN: 14120

European-Finnish (FIN) AF: 0.00794 AC: 2 AN: 252

Middle Eastern (MID) AF: 0.0379 AC: 53 AN: 1400

European-Non Finnish (NFE) AF: 0.00673 AC: 4409 AN: 655272

Other (OTH) AF: 0.0144 AC: 337 AN: 23428

GnomAD4 genome AF: 0.0104 AC: 1577 AN: 152316 Hom.: 21 Cov.: 31 AF XY: 0.0112 AC XY: 833 AN XY: 74468

African (AFR) AF: 0.00147 AC: 61 AN: 41564

American (AMR) AF: 0.0159 AC: 243 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0648 AC: 225 AN: 3472

East Asian (EAS) AF: 0.0216 AC: 112 AN: 5180

South Asian (SAS) AF: 0.0360 AC: 174 AN: 4828

European-Finnish (FIN) AF: 0.0127 AC: 135 AN: 10620

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00851 AC: 579 AN: 68022

Other (OTH) AF: 0.0189 AC: 40 AN: 2116

Alfa AF: 0.00379 Hom.: 0

Bravo AF: 0.00997

Asia WGS AF: 0.0440 AC: 155 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	5.6
DANN	Benign	0.91
PhyloP100		-0.23
PromoterAI		-0.042	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: rs10482603; hg19: chr5-142784613;