rs6198

Variant names:

Germline classification Cancer classification (beta)

Variant summary

Our verdict is . The variant received -12 ACMG points: 0P and 12B. BA1BP4_ModerateBP6_Moderate

The NM_000176.3(NR3C1):c.*3833A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.116 (AC=17,729) in the gnomAD database across 152,190 control chromosomes, including 1,343 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.164. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★).

Frequency

Genomes: 𝑓 0.12 ( 1343 hom., cov: 32)

Failed GnomAD Quality Control

Consequence

NR3C1
NM_000176.3 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.15

Publications

206 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: Laboratory for Molecular Medicine, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia

NR3C1 links:

ENSG00000300303 (HGNC:):

ENSG00000300303 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000176.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

BP6

ClinVar 1-star benign — moderate (BP6); ClinVar germline classification: Benign/Likely Benign, 1 star(s).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.1636 — exceeds 5%% threshold (BA1 applied)

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	Effect	Exon Rank	Protein	UniProt
NR3C1	NM_000176.3	MANE Select	c.*3833A>G	3_prime_UTR	Exon 9 of 9	NP_000167.1	P04150-1
NR3C1	NM_001024094.2		c.*3833A>G	3_prime_UTR	Exon 9 of 9	NP_001019265.1	E5KQF6
NR3C1	NM_001364183.2		c.*3833A>G	3_prime_UTR	Exon 10 of 10	NP_001351112.1	P04150-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NR3C1	ENST00000394464.7	TSL:1 MANE Select	c.*3833A>G	3_prime_UTR	Exon 9 of 9	ENSP00000377977.2	P04150-1
NR3C1	ENST00000415690.6	TSL:1	c.*1308A>G	3_prime_UTR	Exon 9 of 9	ENSP00000387672.2	P04150-2
NR3C1	ENST00000343796.6	TSL:5	c.*3833A>G	3_prime_UTR	Exon 9 of 9	ENSP00000343205.2	P04150-1

Frequencies

GnomAD3 genomes

AF:

0.117

AC:

17741

AN:

152072

Hom.:

1349

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0468

Gnomad AMI

AF:

0.0888

Gnomad AMR

AF:

0.108

Gnomad ASJ

AF:

0.231

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.157

Gnomad FIN

AF:

0.0778

Gnomad MID

AF:

0.291

Gnomad NFE

AF:

0.166

Gnomad OTH

AF:

0.137

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AC:

AN:

Hom.:

Cov.:

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.116

AC:

17729

AN:

152190

Hom.:

1343

Cov.:

AF XY:

0.113

AC XY:

8398

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.0467

AC:

1939

AN:

41540

American (AMR)

AF:

0.108

AC:

1651

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.231

AC:

800

AN:

3470

East Asian (EAS)

AF:

0.00173

AC:

AN:

5190

South Asian (SAS)

AF:

0.157

AC:

759

AN:

4826

European-Finnish (FIN)

AF:

0.0778

AC:

824

AN:

10592

Middle Eastern (MID)

AF:

0.289

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.166

AC:

11294

AN:

67984

Other (OTH)

AF:

0.136

AC:

287

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

788

1576

2363

3151

3939

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

202

404

606

808

1010

<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:

0.150

Hom.:

5081

Bravo

AF:

0.114

Asia WGS

AF:

0.0740

AC:

258

AN:

3470

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.000131

AC:

AN:

121920

Turkish Variome

AF:

0.257

AC:

397

AN:

1546

Hom.:

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.00123

AC:

AN:

8960

Hom.:

ABraOM SABE-WGS-1171

AF:

0.135

AC:

316

AN:

2342

Hom.:

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Glucocorticoid resistance (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.79

PhyloP100

1.1

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over