5-143282198-C-A

Variant names:

• chr5-143282198-C-A
• rs10482704
• NM_000176.3:c.2182-157G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000176.3(NR3C1):​c.2182-157G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 152,238 control chromosomes in the GnomAD database, including 29 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 0.012 (29 hom., cov: 31)
• Consequence: NR3C1 NM_000176.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.134
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0116 (1772/152238) while in subpopulation NFE AF = 0.0204 (1386/68002). AF 95% confidence interval is 0.0195. There are 29 homozygotes in GnomAd4. There are 767 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1772 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR3C1	NM_000176.3	c.2182-157G>T		intron_variant	Intron 8 of 8	ENST00000394464.7	NP_000167.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR3C1	ENST00000394464.7	c.2182-157G>T		intron_variant	Intron 8 of 8	1	NM_000176.3	ENSP00000377977.2

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1770 AN: 152120 Hom.: 29 Cov.: 31

Gnomad AFR AF: 0.00328

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00952

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0133

Gnomad FIN AF: 0.00660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0204

Gnomad OTH AF: 0.00717

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

GnomAD4 genome AF: 0.0116 AC: 1772 AN: 152238 Hom.: 29 Cov.: 31 AF XY: 0.0103 AC XY: 767 AN XY: 74432

African (AFR) AF: 0.00327 AC: 136 AN: 41564

American (AMR) AF: 0.00419 AC: 64 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00952 AC: 33 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.0137 AC: 66 AN: 4814

European-Finnish (FIN) AF: 0.00660 AC: 70 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0204 AC: 1386 AN: 68002

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.0152 Hom.: 38

Bravo AF: 0.0111

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.7
DANN	Benign	0.72
PhyloP100		0.13
Mutation Taster		=100/0	polymorphism

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: rs10482704; hg19: chr5-142661763;