rs4244032

Variant names:

• chr5-143415160-A-G
• rs4244032
• ENST00000504572.5:c.-13-14308T>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.-13-14308T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 152,156 control chromosomes in the GnomAD database, including 2,307 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 (2307 hom., cov: 33)
• Consequence: NR3C1 NM_001364183.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.178
• Publications: 11 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)

ENSG00000305502 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.197 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.-13-14308T>C		intron	N/A	NP_001351112.1	P04150-3
	NR3C1	NM_001018074.1		c.-13-14308T>C		intron	N/A	NP_001018084.1	P04150-1
	NR3C1	NM_001018075.1		c.-13-14308T>C		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.-13-14308T>C		intron	N/A	ENSP00000422518.1	P04150-3
	NR3C1	ENST00000870492.1		c.-13-14308T>C		intron	N/A	ENSP00000540551.1
	NR3C1	ENST00000343796.6	TSL:5	c.-13-14308T>C		intron	N/A	ENSP00000343205.2	P04150-1

Frequencies

GnomAD3 genomes AF: 0.165 AC: 25089 AN: 152038 Hom.: 2312 Cov.: 33

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.117

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.236

Gnomad EAS AF: 0.00192

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.182

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.165 AC: 25089 AN: 152156 Hom.: 2307 Cov.: 33 AF XY: 0.160 AC XY: 11928 AN XY: 74412

African (AFR) AF: 0.141 AC: 5860 AN: 41498

American (AMR) AF: 0.145 AC: 2216 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 820 AN: 3470

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5184

South Asian (SAS) AF: 0.183 AC: 879 AN: 4816

European-Finnish (FIN) AF: 0.108 AC: 1150 AN: 10600

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.200 AC: 13564 AN: 67976

Other (OTH) AF: 0.179 AC: 379 AN: 2116

Alfa AF: 0.183 Hom.: 564

Bravo AF: 0.168

Asia WGS AF: 0.0830 AC: 293 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.76
DANN	Benign	0.74
PhyloP100		0.18
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: rs4244032; hg19: chr5-142794725; COSMIC: COSV59429660;