rs10482665

Variant names:

• chr5-143314736-A-G
• rs10482665
• NM_000176.3:c.1185-568T>C

Variant summary

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

The NM_001024094.2(NR3C1):​c.1185-568T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 152,212 control chromosomes in the GnomAD database, including 1,486 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 (1486 hom., cov: 32)
• Consequence: NR3C1 NM_001024094.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.32
• Publications: 2 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001024094.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C1	NM_000176.3	MANE Select	c.1185-568T>C		intron	N/A	NP_000167.1
	NR3C1	NM_001024094.2		c.1185-568T>C		intron	N/A	NP_001019265.1
	NR3C1	NM_001364183.2		c.1185-568T>C		intron	N/A	NP_001351112.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C1	ENST00000394464.7	TSL:1 MANE Select	c.1185-568T>C		intron	N/A	ENSP00000377977.2
	NR3C1	ENST00000231509.7	TSL:1	c.1185-568T>C		intron	N/A	ENSP00000231509.3
	NR3C1	ENST00000504572.5	TSL:1	c.1185-568T>C		intron	N/A	ENSP00000422518.1

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19773 AN: 152096 Hom.: 1491 Cov.: 32

Gnomad AFR AF: 0.0914

Gnomad AMI AF: 0.0881

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.160

Gnomad FIN AF: 0.0776

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.151

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

GnomAD4 genome AF: 0.130 AC: 19770 AN: 152212 Hom.: 1486 Cov.: 32 AF XY: 0.126 AC XY: 9365 AN XY: 74408

African (AFR) AF: 0.0913 AC: 3794 AN: 41550

American (AMR) AF: 0.115 AC: 1760 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.231 AC: 800 AN: 3468

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5186

South Asian (SAS) AF: 0.160 AC: 772 AN: 4828

European-Finnish (FIN) AF: 0.0776 AC: 822 AN: 10596

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.167 AC: 11331 AN: 67988

Other (OTH) AF: 0.149 AC: 316 AN: 2114

Alfa AF: 0.141 Hom.: 220

Bravo AF: 0.130

Asia WGS AF: 0.0790 AC: 276 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.035
DANN	Benign	0.62
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs10482665; hg19: chr5-142694301;