Variant rs6190 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_000176.3(NR3C1):c.68G>C(p.Arg23Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R23K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

NR3C1
NM_000176.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.77

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a modified_residue Omega-N-methylarginine (size 0) in uniprot entity GCR_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2032611).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR3C1	NM_000176.3 linkuse as main transcript	c.68G>C	p.Arg23Thr	missense_variant	2/9	ENST00000394464.7	NP_000167.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR3C1	ENST00000394464.7 linkuse as main transcript	c.68G>C	p.Arg23Thr	missense_variant	2/9	1	NM_000176.3	ENSP00000377977	A1	P04150-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251468

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.045

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.31

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

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.91

.;D;D;D;.;.;D;.;.;.;.;D;D

M_CAP

Benign

0.049

MetaRNN

Benign

0.20

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

MetaSVM

Uncertain

-0.27

MutationAssessor

Uncertain

2.3

M;M;M;M;M;M;M;M;.;.;.;.;.

MutationTaster

Benign

0.90

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

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.37

N;N;N;N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.11

Sift

Uncertain

0.016

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

Sift4G

Benign

0.58

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

Polyphen

0.67

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

Vest4

0.36

MutPred

0.16

Loss of MoRF binding (P = 0.0654);Loss of MoRF binding (P = 0.0654);Loss of MoRF binding (P = 0.0654);Loss of MoRF binding (P = 0.0654);Loss of MoRF binding (P = 0.0654);Loss of MoRF binding (P = 0.0654);Loss of MoRF binding (P = 0.0654);Loss of MoRF binding (P = 0.0654);Loss of MoRF binding (P = 0.0654);Loss of MoRF binding (P = 0.0654);Loss of MoRF binding (P = 0.0654);Loss of MoRF binding (P = 0.0654);Loss of MoRF binding (P = 0.0654);

MVP

0.92

MPC

0.14

ClinPred

0.35

GERP RS

5.2

Varity_R

0.16

gMVP

0.26

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over