5-143404562-A-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001364183.2(NR3C1):​c.-13-3710T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000122 in 822,822 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 23)
  • Exomes 𝑓: 0.0000012 (0 hom.)
• Consequence: NR3C1 NM_001364183.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.945
• 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

LOC128966704 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).

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>G		intron	N/A	NP_001351112.1
	NR3C1	NM_001018074.1		c.-13-3710T>G		intron	N/A	NP_001018084.1
	NR3C1	NM_001018075.1		c.-13-3710T>G		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>G		intron	N/A	ENSP00000422518.1
	NR3C1	ENST00000502892.5	TSL:1	c.-14+57T>G		intron	N/A	ENSP00000420856.1
	NR3C1	ENST00000514699.1	TSL:1	c.-14+588T>G		intron	N/A	ENSP00000426478.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000122 AC: 1 AN: 822822 Hom.: 0 Cov.: 17 AF XY: 0.00 AC XY: 0 AN XY: 380188

African (AFR) AF: 0.0000642 AC: 1 AN: 15574

American (AMR) AF: 0.00 AC: 0 AN: 972

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5124

East Asian (EAS) AF: 0.00 AC: 0 AN: 3576

South Asian (SAS) AF: 0.00 AC: 0 AN: 16318

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 268

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1604

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 752442

Other (OTH) AF: 0.00 AC: 0 AN: 26944

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	16
DANN	Benign	0.49
PhyloP100		0.94
PromoterAI		-0.030	Neutral

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;