5-143404562-A-G

Variant names:

• chr5-143404562-A-G
• rs3806854
• ENST00000504572.5:c.-13-3710T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001364183.2(NR3C1):​c.-13-3710T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 956,486 control chromosomes in the GnomAD database, including 11,975 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 0.16 (1745 hom., cov: 23)
  • Exomes 𝑓: 0.16 (10230 hom.)
• Consequence: NR3C1 NM_001364183.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.945
• Publications: 5 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

LOC128966704 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

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.-13-3710T>C		intron	N/A	NP_001351112.1
	NR3C1	NM_001018074.1		c.-13-3710T>C		intron	N/A	NP_001018084.1
	NR3C1	NM_001018075.1		c.-13-3710T>C		intron	N/A	NP_001018085.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C1	ENST00000504572.5	TSL:1	c.-13-3710T>C		intron	N/A	ENSP00000422518.1
	NR3C1	ENST00000502892.5	TSL:1	c.-14+57T>C		intron	N/A	ENSP00000420856.1
	NR3C1	ENST00000514699.1	TSL:1	c.-14+588T>C		intron	N/A	ENSP00000426478.1

Frequencies

GnomAD3 genomes AF: 0.158 AC: 21522 AN: 136554 Hom.: 1742 Cov.: 23

Gnomad AFR AF: 0.184

Gnomad AMI AF: 0.247

Gnomad AMR AF: 0.0956

Gnomad ASJ AF: 0.0650

Gnomad EAS AF: 0.0870

Gnomad SAS AF: 0.0422

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.0238

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.129

GnomAD4 exome AF: 0.156 AC: 128102 AN: 819840 Hom.: 10230 Cov.: 17 AF XY: 0.156 AC XY: 58992 AN XY: 378782

African (AFR) AF: 0.170 AC: 2635 AN: 15530

American (AMR) AF: 0.0813 AC: 79 AN: 972

Ashkenazi Jewish (ASJ) AF: 0.0637 AC: 326 AN: 5120

East Asian (EAS) AF: 0.0799 AC: 285 AN: 3568

South Asian (SAS) AF: 0.0326 AC: 532 AN: 16300

European-Finnish (FIN) AF: 0.199 AC: 53 AN: 266

Middle Eastern (MID) AF: 0.0281 AC: 45 AN: 1604

European-Non Finnish (NFE) AF: 0.161 AC: 120455 AN: 749616

Other (OTH) AF: 0.137 AC: 3692 AN: 26864

GnomAD4 genome AF: 0.158 AC: 21554 AN: 136646 Hom.: 1745 Cov.: 23 AF XY: 0.158 AC XY: 10379 AN XY: 65660

African (AFR) AF: 0.184 AC: 6830 AN: 37030

American (AMR) AF: 0.0954 AC: 1227 AN: 12858

Ashkenazi Jewish (ASJ) AF: 0.0650 AC: 216 AN: 3324

East Asian (EAS) AF: 0.0869 AC: 347 AN: 3992

South Asian (SAS) AF: 0.0409 AC: 155 AN: 3786

European-Finnish (FIN) AF: 0.238 AC: 1977 AN: 8294

Middle Eastern (MID) AF: 0.0221 AC: 6 AN: 272

European-Non Finnish (NFE) AF: 0.161 AC: 10337 AN: 64310

Other (OTH) AF: 0.128 AC: 246 AN: 1916

Alfa AF: 0.0595 Hom.: 63

Asia WGS AF: 0.0670 AC: 228 AN: 3420

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	17
DANN	Benign	0.44
PhyloP100		0.94
PromoterAI		0.40	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs3806854; hg19: chr5-142784127;