rs6192

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000176.3(NR3C1):c.193T>G(p.Phe65Val) variant causes a missense change. The variant allele was found at a frequency of 0.000787 in 1,614,040 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0044 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00041 ( 2 hom. )

Consequence

NR3C1
NM_000176.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 4.53

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008410096).

BP6

Variant 5-143400647-A-C is Benign according to our data. Variant chr5-143400647-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 722582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00437 (665/152314) while in subpopulation AFR AF= 0.0152 (633/41568). AF 95% confidence interval is 0.0142. There are 2 homozygotes in gnomad4. There are 327 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR3C1	NM_000176.3 linkuse as main transcript	c.193T>G	p.Phe65Val	missense_variant	2/9	ENST00000394464.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR3C1	ENST00000394464.7 linkuse as main transcript	c.193T>G	p.Phe65Val	missense_variant	2/9	1	NM_000176.3	A1	P04150-1

Frequencies

GnomAD3 genomes

AF:

0.00434

AC:

660

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0152

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00336

GnomAD3 exomes

AF:

0.000970

AC:

244

AN:

251438

Hom.:

AF XY:

0.000743

AC XY:

101

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.0137

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000414

AC:

605

AN:

1461726

Hom.:

Cov.:

AF XY:

0.000367

AC XY:

267

AN XY:

727120

show subpopulations

Gnomad4 AFR exome

AF:

0.0148

Gnomad4 AMR exome

AF:

0.000581

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.00113

GnomAD4 genome

AF:

0.00437

AC:

665

AN:

152314

Hom.:

Cov.:

AF XY:

0.00439

AC XY:

327

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.0152

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00332

Alfa

AF:

0.000735

Hom.:

Bravo

AF:

0.00474

ESP6500AA

AF:

0.0143

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00126

AC:

153

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glucocorticoid resistance

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.40

Cadd

Benign

Dann

Benign

0.94

DEOGEN2

Benign

0.15

T;T;.;.;.;.;.;T;T;T;T;T;T

Eigen

Benign

0.018

Eigen_PC

Benign

0.12

FATHMM_MKL

Benign

0.74

MetaRNN

Benign

0.0084

T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;L;L;L;L;L;L;L;.;.;.;.;.

MutationTaster

Benign

0.92

D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.010

N;N;N;N;N;N;N;N;D;D;D;D;D

REVEL

Benign

0.081

Sift

Benign

0.33

T;T;T;T;T;T;T;T;D;D;D;D;D

Sift4G

Benign

0.58

T;T;T;T;T;T;T;T;.;.;.;.;T

Polyphen

0.68

P;P;.;.;.;.;.;P;.;.;.;.;.

Vest4

0.61

MVP

0.69

MPC

0.14

ClinPred

0.016

GERP RS

4.8

Varity_R

0.070

gMVP

0.16

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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