rs6194

chr5-143298796-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000176.3(NR3C1):c.1764C>T(p.His588=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00355 in 1,613,416 control chromosomes in the GnomAD database, including 150 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (21 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (129 hom.)
• Consequence: NR3C1 NM_000176.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.09

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 5-143298796-G-A is Benign according to our data. Variant chr5-143298796-G-A is described in ClinVar as [Benign]. Clinvar id is 351368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-143298796-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.09 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.065 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR3C1	NM_000176.3	c.1764C>T	p.His588=	synonymous_variant	6/9	ENST00000394464.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR3C1	ENST00000394464.7	c.1764C>T	p.His588=	synonymous_variant	6/9	1	NM_000176.3	A1

Frequencies

GnomAD3 genomes AF: 0.00480 AC: 729 AN: 151988 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.000798

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0710

Gnomad SAS AF: 0.00996

Gnomad FIN AF: 0.0225

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00836 AC: 2099 AN: 251198 Hom.: 45 AF XY: 0.00802 AC XY: 1089 AN XY: 135784

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0700

Gnomad SAS exome AF: 0.00980

Gnomad FIN exome AF: 0.0202

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00342 AC: 4996 AN: 1461310 Hom.: 129 Cov.: 32 AF XY: 0.00347 AC XY: 2525 AN XY: 726974

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0697

Gnomad4 SAS exome AF: 0.00892

Gnomad4 FIN exome AF: 0.0192

Gnomad4 NFE exome AF: 0.0000872

Gnomad4 OTH exome AF: 0.00522

GnomAD4 genome AF: 0.00478 AC: 727 AN: 152106 Hom.: 21 Cov.: 32 AF XY: 0.00628 AC XY: 467 AN XY: 74336

Gnomad4 AFR AF: 0.000796

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0710

Gnomad4 SAS AF: 0.00976

Gnomad4 FIN AF: 0.0225

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00190 Hom.: 10

Bravo AF: 0.00314

Asia WGS AF: 0.0460 AC: 161 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glucocorticoid resistance Benign:1

Benign, 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 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
Cadd	Benign	5.9
Dann	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs6194; hg19: chr5-142678361; COSMIC: COSV99196093; COSMIC: COSV99196093;