rs6194

Positions:

chr5-143298796-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000176.3(NR3C1):c.1764C>T(p.His588His) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.09

Variant links:

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 links:

NR3C1 (HGNC:):

NR3C1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
NR3C1	NM_000176.3 linkuse as main transcript	c.1764C>T	p.His588His	synonymous_variant	6/9	ENST00000394464.7	NP_000167.1	P04150-1F1D8N4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR3C1	ENST00000394464.7 linkuse as main transcript	c.1764C>T	p.His588His	synonymous_variant	6/9	1	NM_000176.3	ENSP00000377977.2		P04150-1

Frequencies

GnomAD3 genomes

AF:

0.00480

AC:

729

AN:

151988

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00802

AC XY:

1089

AN XY:

135784

show subpopulations

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.:

AF XY:

0.00347

AC XY:

2525

AN XY:

726974

show subpopulations

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.:

Cov.:

AF XY:

0.00628

AC XY:

467

AN XY:

74336

show subpopulations

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.:

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

LINK: link

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

Labcorp Genetics (formerly Invitae), Labcorp

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over