rs6198

Positions:

• chr5-143278056-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_000176.3(NR3C1):​c.*3833A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 152,190 control chromosomes in the GnomAD database, including 1,343 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.12 (1343 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: NR3C1 NM_000176.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.15

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 5-143278056-T-C is Benign according to our data. Variant chr5-143278056-T-C is described in ClinVar as [Benign]. Clinvar id is 351314.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR3C1	NM_000176.3	c.*3833A>G		3_prime_UTR_variant	9/9	ENST00000394464.7	NP_000167.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR3C1	ENST00000394464.7	c.*3833A>G		3_prime_UTR_variant	9/9	1	NM_000176.3	ENSP00000377977	A1
NR3C1	ENST00000415690.6	c.*1308A>G		3_prime_UTR_variant	9/9	1		ENSP00000387672
NR3C1	ENST00000343796.6	c.*3833A>G		3_prime_UTR_variant	9/9	5		ENSP00000343205	A1

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17741 AN: 152072 Hom.: 1349 Cov.: 32

Gnomad AFR AF: 0.0468

Gnomad AMI AF: 0.0888

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.0778

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.137

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.116 AC: 17729 AN: 152190 Hom.: 1343 Cov.: 32 AF XY: 0.113 AC XY: 8398 AN XY: 74394

Gnomad4 AFR AF: 0.0467

Gnomad4 AMR AF: 0.108

Gnomad4 ASJ AF: 0.231

Gnomad4 EAS AF: 0.00173

Gnomad4 SAS AF: 0.157

Gnomad4 FIN AF: 0.0778

Gnomad4 NFE AF: 0.166

Gnomad4 OTH AF: 0.136

Alfa AF: 0.161 Hom.: 3545

Bravo AF: 0.114

Asia WGS AF: 0.0740 AC: 258 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Glucocorticoid resistance Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	15
DANN	Benign	0.79

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

Publications

LitVar

Other links and lift over

dbSNP: rs6198; hg19: chr5-142657621;