dbSNP rs6189: NR3C1:p.Glu22Glu (chr5-143400774-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000176.3(NR3C1):c.66G>A(p.Glu22Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.024 in 1,614,150 control chromosomes in the GnomAD database, including 590 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 42 hom., cov: 32)

Exomes 𝑓: 0.025 ( 548 hom. )

Consequence

NR3C1
NM_000176.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.387

Publications

130 publications found

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 Gene-Disease associations (from GenCC):

glucocorticoid resistance
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae)

NR3C1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 5-143400774-C-T is Benign according to our data. Variant chr5-143400774-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 155925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.387 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0166 (2535/152308) while in subpopulation NFE AF = 0.0274 (1863/68028). AF 95% confidence interval is 0.0264. There are 42 homozygotes in GnomAd4. There are 1168 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2535 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000176.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NR3C1	NM_000176.3	MANE Select	c.66G>A	p.Glu22Glu	synonymous	Exon 2 of 9	NP_000167.1	P04150-1
NR3C1	NM_001024094.2		c.66G>A	p.Glu22Glu	synonymous	Exon 2 of 9	NP_001019265.1	E5KQF6
NR3C1	NM_001364183.2		c.66G>A	p.Glu22Glu	synonymous	Exon 3 of 10	NP_001351112.1	P04150-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NR3C1	ENST00000394464.7	TSL:1 MANE Select	c.66G>A	p.Glu22Glu	synonymous	Exon 2 of 9	ENSP00000377977.2	P04150-1
NR3C1	ENST00000231509.7	TSL:1	c.66G>A	p.Glu22Glu	synonymous	Exon 2 of 9	ENSP00000231509.3	P04150-3
NR3C1	ENST00000504572.5	TSL:1	c.66G>A	p.Glu22Glu	synonymous	Exon 3 of 10	ENSP00000422518.1	P04150-3

Frequencies

GnomAD3 genomes

AF:

0.0166

AC:

2533

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00456

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00621

Gnomad ASJ

AF:

0.0184

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0139

Gnomad FIN

AF:

0.0209

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0274

Gnomad OTH

AF:

0.0124

GnomAD2 exomes

AF:

0.0183

AC:

4603

AN:

251466

AF XY:

0.0191

show subpopulations

Gnomad AFR exome

AF:

0.00443

Gnomad AMR exome

AF:

0.00676

Gnomad ASJ exome

AF:

0.0200

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0243

Gnomad NFE exome

AF:

0.0263

Gnomad OTH exome

AF:

0.0181

GnomAD4 exome

AF:

0.0248

AC:

36200

AN:

1461842

Hom.:

548

Cov.:

AF XY:

0.0245

AC XY:

17835

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.00355

AC:

119

AN:

33478

American (AMR)

AF:

0.00720

AC:

322

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0195

AC:

510

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0152

AC:

1308

AN:

86258

European-Finnish (FIN)

AF:

0.0223

AC:

1192

AN:

53410

Middle Eastern (MID)

AF:

0.0158

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0283

AC:

31435

AN:

1111972

Other (OTH)

AF:

0.0202

AC:

1223

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

1966

3932

5898

7864

9830

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1158

2316

3474

4632

5790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0166

AC:

2535

AN:

152308

Hom.:

Cov.:

AF XY:

0.0157

AC XY:

1168

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00455

AC:

189

AN:

41568

American (AMR)

AF:

0.00620

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.0184

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.0143

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0209

AC:

221

AN:

10596

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0274

AC:

1863

AN:

68028

Other (OTH)

AF:

0.0123

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

128

256

385

513

641

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0217

Hom.:

Bravo

AF:

0.0149

Asia WGS

AF:

0.00751

AC:

AN:

3478

EpiCase

AF:

0.0253

EpiControl

AF:

0.0254

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Glucocorticoid resistance (2)

not provided (2)

NR3C1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

7.1

(source)

DANN

Benign

0.82

PhyloP100

0.39

PromoterAI

0.070

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over