chr5-143403956-A-G

Variant names:

• chr5-143403956-A-G
• rs10482605
• ENST00000504572.5:c.-13-3104T>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.-13-3104T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 984,588 control chromosomes in the GnomAD database, including 12,733 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 0.13 (1513 hom., cov: 32)
  • Exomes 𝑓: 0.16 (11220 hom.)
• Consequence: NR3C1 NM_001364183.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.312
• Publications: 32 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: Labcorp Genetics (formerly Invitae), Orphanet, Laboratory for Molecular Medicine, Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.166 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.-13-3104T>C		intron	N/A	NP_001351112.1	P04150-3
	NR3C1	NM_001364184.2		c.-14+420T>C		intron	N/A	NP_001351113.1	E5KQF6
	NR3C1	NM_001018074.1		c.-13-3104T>C		intron	N/A	NP_001018084.1	P04150-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C1	ENST00000504572.5	TSL:1	c.-13-3104T>C		intron	N/A	ENSP00000422518.1	P04150-3
	NR3C1	ENST00000503201.1	TSL:1	c.-14+420T>C		intron	N/A	ENSP00000427672.1	P04150-1
	NR3C1	ENST00000502892.5	TSL:1	c.-14+663T>C		intron	N/A	ENSP00000420856.1	Q3MSN4

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19849 AN: 151088 Hom.: 1519 Cov.: 32

Gnomad AFR AF: 0.0914

Gnomad AMI AF: 0.0888

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.233

Gnomad EAS AF: 0.00175

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.0770

Gnomad MID AF: 0.322

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.158

GnomAD4 exome AF: 0.163 AC: 135713 AN: 833390 Hom.: 11220 Cov.: 32 AF XY: 0.164 AC XY: 62975 AN XY: 384918

African (AFR) AF: 0.0896 AC: 1415 AN: 15792

American (AMR) AF: 0.127 AC: 125 AN: 986

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 1170 AN: 5156

East Asian (EAS) AF: 0.00110 AC: 4 AN: 3638

South Asian (SAS) AF: 0.166 AC: 2745 AN: 16560

European-Finnish (FIN) AF: 0.103 AC: 31 AN: 302

Middle Eastern (MID) AF: 0.277 AC: 449 AN: 1620

European-Non Finnish (NFE) AF: 0.165 AC: 125399 AN: 762020

Other (OTH) AF: 0.160 AC: 4375 AN: 27316

GnomAD4 genome AF: 0.131 AC: 19836 AN: 151198 Hom.: 1513 Cov.: 32 AF XY: 0.127 AC XY: 9390 AN XY: 73886

African (AFR) AF: 0.0912 AC: 3762 AN: 41270

American (AMR) AF: 0.119 AC: 1811 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 807 AN: 3464

East Asian (EAS) AF: 0.00175 AC: 9 AN: 5132

South Asian (SAS) AF: 0.157 AC: 758 AN: 4816

European-Finnish (FIN) AF: 0.0770 AC: 794 AN: 10308

Middle Eastern (MID) AF: 0.322 AC: 94 AN: 292

European-Non Finnish (NFE) AF: 0.168 AC: 11394 AN: 67676

Other (OTH) AF: 0.155 AC: 326 AN: 2102

Alfa AF: 0.144 Hom.: 223

Bravo AF: 0.131

Asia WGS AF: 0.0750 AC: 260 AN: 3452

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.9
DANN	Benign	0.35
PhyloP100		0.31
PromoterAI		-0.019	Neutral
Mutation Taster		=99/1	polymorphism (auto)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs10482605;

hg19: chr5-142783521;