5-143278591-C-A

Position:

• chr5-143278591-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000176.3(NR3C1):​c.*3298G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.476 in 151,876 control chromosomes in the GnomAD database, including 17,727 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.48 (17725 hom., cov: 31)
  • Exomes 𝑓: 0.42 (2 hom.)
• Consequence: NR3C1 NM_000176.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.125

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 5-143278591-C-A is Benign according to our data. Variant chr5-143278591-C-A is described in ClinVar as [Benign]. Clinvar id is 351321.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.533 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR3C1	NM_000176.3	c.*3298G>T		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.*3298G>T		3_prime_UTR_variant	9/9	1	NM_000176.3	ENSP00000377977	A1
NR3C1	ENST00000415690.6	c.*773G>T		3_prime_UTR_variant	9/9	1		ENSP00000387672
NR3C1	ENST00000343796.6	c.*3298G>T		3_prime_UTR_variant	9/9	5		ENSP00000343205	A1

Frequencies

GnomAD3 genomes AF: 0.476 AC: 72184 AN: 151732 Hom.: 17710 Cov.: 31

Gnomad AFR AF: 0.439

Gnomad AMI AF: 0.614

Gnomad AMR AF: 0.383

Gnomad ASJ AF: 0.475

Gnomad EAS AF: 0.245

Gnomad SAS AF: 0.387

Gnomad FIN AF: 0.497

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.538

Gnomad OTH AF: 0.463

GnomAD4 exome AF: 0.417 AC: 10 AN: 24 Hom.: 2 Cov.: 0 AF XY: 0.400 AC XY: 8 AN XY: 20

Gnomad4 AFR exome AF: 1.00

Gnomad4 NFE exome AF: 0.364

GnomAD4 genome AF: 0.476 AC: 72238 AN: 151852 Hom.: 17725 Cov.: 31 AF XY: 0.469 AC XY: 34780 AN XY: 74208

Gnomad4 AFR AF: 0.439

Gnomad4 AMR AF: 0.382

Gnomad4 ASJ AF: 0.475

Gnomad4 EAS AF: 0.244

Gnomad4 SAS AF: 0.386

Gnomad4 FIN AF: 0.497

Gnomad4 NFE AF: 0.538

Gnomad4 OTH AF: 0.462

Alfa AF: 0.379 Hom.: 1033

Bravo AF: 0.466

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

Jan 12, 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	-0.88
CADD	Benign	0.58
DANN	Benign	0.52

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: rs6191; hg19: chr5-142658156;