5-143278012-G-A

Position:

• chr5-143278012-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_000176.3(NR3C1):​c.*3877C>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 0.00281 in 152,034 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: NR3C1 NM_000176.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.35

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 Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00281 (427/152034) while in subpopulation NFE AF= 0.00455 (309/67978). AF 95% confidence interval is 0.00413. There are 1 homozygotes in gnomad4. There are 191 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR3C1	NM_000176.3	c.*3877C>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.*3877C>T		3_prime_UTR_variant	9/9	1	NM_000176.3	ENSP00000377977	A1
NR3C1	ENST00000415690.6	c.*1352C>T		3_prime_UTR_variant	9/9	1		ENSP00000387672
NR3C1	ENST00000343796.6	c.*3877C>T		3_prime_UTR_variant	9/9	5		ENSP00000343205	A1

Frequencies

GnomAD3 genomes AF: 0.00281 AC: 427 AN: 151916 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000895

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.00199

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00455

Gnomad OTH AF: 0.00288

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: 0.00281 AC: 427 AN: 152034 Hom.: 1 Cov.: 32 AF XY: 0.00257 AC XY: 191 AN XY: 74318

Gnomad4 AFR AF: 0.000892

Gnomad4 AMR AF: 0.00177

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.00199

Gnomad4 NFE AF: 0.00455

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.00417 Hom.: 3

Bravo AF: 0.00291

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Glucocorticoid resistance Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	12
DANN	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs10482716; hg19: chr5-142657577;