Genetic Variant NM_000176.3:c.2298T>C (chr5-143281925-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000176.3(NR3C1):c.2298T>C(p.Asn766Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 1,613,080 control chromosomes in the GnomAD database, including 19,890 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 1921 hom., cov: 31)

Exomes 𝑓: 0.15 ( 17969 hom. )

Consequence

NR3C1
NM_000176.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.67

Publications

79 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:

ENSG00000300303 (HGNC:):

ENSG00000300303 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=-0.51).

BP6

Variant 5-143281925-A-G is Benign according to our data. Variant chr5-143281925-A-G is described in ClinVar as Benign. ClinVar VariationId is 351364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.67 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

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.2298T>C	p.Asn766Asn	synonymous	Exon 9 of 9	NP_000167.1	P04150-1
NR3C1	NM_001024094.2		c.2301T>C	p.Asn767Asn	synonymous	Exon 9 of 9	NP_001019265.1	E5KQF6
NR3C1	NM_001364183.2		c.2301T>C	p.Asn767Asn	synonymous	Exon 10 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.2298T>C	p.Asn766Asn	synonymous	Exon 9 of 9	ENSP00000377977.2	P04150-1
NR3C1	ENST00000231509.7	TSL:1	c.2301T>C	p.Asn767Asn	synonymous	Exon 9 of 9	ENSP00000231509.3	P04150-3
NR3C1	ENST00000504572.5	TSL:1	c.2301T>C	p.Asn767Asn	synonymous	Exon 10 of 10	ENSP00000422518.1	P04150-3

Frequencies

GnomAD3 genomes

AF:

0.152

AC:

23036

AN:

152052

Hom.:

1917

Cov.:

show subpopulations

Gnomad AFR

AF:

0.178

Gnomad AMI

AF:

0.242

Gnomad AMR

AF:

0.0909

Gnomad ASJ

AF:

0.0655

Gnomad EAS

AF:

0.0725

Gnomad SAS

AF:

0.0334

Gnomad FIN

AF:

0.203

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.160

Gnomad OTH

AF:

0.125

GnomAD2 exomes

AF:

0.124

AC:

31150

AN:

250760

AF XY:

0.121

show subpopulations

Gnomad AFR exome

AF:

0.178

Gnomad AMR exome

AF:

0.0648

Gnomad ASJ exome

AF:

0.0705

Gnomad EAS exome

AF:

0.0709

Gnomad FIN exome

AF:

0.201

Gnomad NFE exome

AF:

0.158

Gnomad OTH exome

AF:

0.127

GnomAD4 exome

AF:

0.150

AC:

219156

AN:

1460910

Hom.:

17969

Cov.:

AF XY:

0.146

AC XY:

105980

AN XY:

726802

show subpopulations

African (AFR)

AF:

0.177

AC:

5926

AN:

33430

American (AMR)

AF:

0.0704

AC:

3147

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.0716

AC:

1870

AN:

26114

East Asian (EAS)

AF:

0.0705

AC:

2792

AN:

39618

South Asian (SAS)

AF:

0.0325

AC:

2805

AN:

86246

European-Finnish (FIN)

AF:

0.203

AC:

10845

AN:

53384

Middle Eastern (MID)

AF:

0.0257

AC:

148

AN:

5764

European-Non Finnish (NFE)

AF:

0.165

AC:

183189

AN:

1111328

Other (OTH)

AF:

0.140

AC:

8434

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

9564

19128

28693

38257

47821

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6420

12840

19260

25680

32100

<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:

0.152

AC:

23070

AN:

152170

Hom.:

1921

Cov.:

AF XY:

0.150

AC XY:

11138

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.178

AC:

7411

AN:

41526

American (AMR)

AF:

0.0908

AC:

1388

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0655

AC:

227

AN:

3468

East Asian (EAS)

AF:

0.0725

AC:

376

AN:

5186

South Asian (SAS)

AF:

0.0324

AC:

156

AN:

4814

European-Finnish (FIN)

AF:

0.203

AC:

2144

AN:

10582

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.160

AC:

10879

AN:

67992

Other (OTH)

AF:

0.124

AC:

262

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

964

1929

2893

3858

4822

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

244

488

732

976

1220

<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:

0.149

Hom.:

6102

Bravo

AF:

0.145

Asia WGS

AF:

0.0740

AC:

258

AN:

3478

EpiCase

AF:

0.145

EpiControl

AF:

0.139

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Glucocorticoid resistance (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

4.8

(source)

DANN

Benign

0.68

PhyloP100

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

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

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