rs10482703

Variant names:

• chr5-143282800-G-GAT
• rs10482703
• NM_000176.3:c.2024-77_2024-76dupAT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_000176.3(NR3C1):​c.2024-77_2024-76dupAT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000561 in 1,407,738 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000069 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000055 (1 hom.)
• Consequence: NR3C1 NM_000176.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.05
• 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

ENSG00000300303 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000686 (10/145814) while in subpopulation AMR AF = 0.000345 (5/14474). AF 95% confidence interval is 0.000135. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 10 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000176.3. 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.2024-77_2024-76dupAT		intron	N/A	NP_000167.1
	NR3C1	NM_001024094.2		c.2027-77_2027-76dupAT		intron	N/A	NP_001019265.1
	NR3C1	NM_001364183.2		c.2027-77_2027-76dupAT		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.2024-76_2024-75insAT		intron	N/A	ENSP00000377977.2
	NR3C1	ENST00000231509.7	TSL:1	c.2027-76_2027-75insAT		intron	N/A	ENSP00000231509.3
	NR3C1	ENST00000504572.5	TSL:1	c.2027-76_2027-75insAT		intron	N/A	ENSP00000422518.1

Frequencies

GnomAD3 genomes AF: 0.0000686 AC: 10 AN: 145814 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000345

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000547 AC: 69 AN: 1261924 Hom.: 1 AF XY: 0.0000537 AC XY: 34 AN XY: 633426

African (AFR) AF: 0.00 AC: 0 AN: 27382

American (AMR) AF: 0.00189 AC: 67 AN: 35424

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23720

East Asian (EAS) AF: 0.00 AC: 0 AN: 37296

South Asian (SAS) AF: 0.0000264 AC: 2 AN: 75718

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37860

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4614

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 967098

Other (OTH) AF: 0.00 AC: 0 AN: 52812

GnomAD4 genome AF: 0.0000686 AC: 10 AN: 145814 Hom.: 0 Cov.: 30 AF XY: 0.0000425 AC XY: 3 AN XY: 70648

African (AFR) AF: 0.000128 AC: 5 AN: 39200

American (AMR) AF: 0.000345 AC: 5 AN: 14474

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3438

East Asian (EAS) AF: 0.00 AC: 0 AN: 5028

South Asian (SAS) AF: 0.00 AC: 0 AN: 4650

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8948

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66886

Other (OTH) AF: 0.00 AC: 0 AN: 1980

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.1

Splicing

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

Other links and lift over

dbSNP: rs10482703; hg19: chr5-142662365;