Genetic Variant NR3C1:c.-13-2851T>C (chr5-143403703-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The ENST00000504572.5(NR3C1):c.-13-2851T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.005 in 983,372 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0038 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0052 ( 9 hom. )

Consequence

NR3C1
ENST00000504572.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.641

Publications

3 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, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

NR3C1 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00377 (567/150546) while in subpopulation NFE AF = 0.0056 (380/67822). AF 95% confidence interval is 0.00514. There are 2 homozygotes in GnomAd4. There are 270 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 567 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000504572.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein
NR3C1	NM_001364183.2	c.-13-2851T>C	intron	N/A	NP_001351112.1
NR3C1	NM_001364184.2	c.-14+673T>C	intron	N/A	NP_001351113.1
NR3C1	NM_001018074.1	c.-13-2851T>C	intron	N/A	NP_001018084.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
NR3C1	ENST00000504572.5	TSL:1	c.-13-2851T>C	intron	N/A	ENSP00000422518.1
NR3C1	ENST00000503201.1	TSL:1	c.-14+673T>C	intron	N/A	ENSP00000427672.1
NR3C1	ENST00000502892.5	TSL:1	c.-14+916T>C	intron	N/A	ENSP00000420856.1

Frequencies

GnomAD3 genomes

AF:

0.00377

AC:

567

AN:

150442

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00122

Gnomad AMI

AF:

0.00440

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.000578

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0106

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00560

Gnomad OTH

AF:

0.00193

GnomAD4 exome

AF:

0.00522

AC:

4349

AN:

832826

Hom.:

Cov.:

AF XY:

0.00530

AC XY:

2040

AN XY:

384650

show subpopulations

African (AFR)

AF:

0.000587

AC:

AN:

15336

American (AMR)

AF:

0.00203

AC:

AN:

984

Ashkenazi Jewish (ASJ)

AF:

0.000388

AC:

AN:

5158

East Asian (EAS)

AF:

0.00

AC:

AN:

3638

South Asian (SAS)

AF:

0.0000607

AC:

AN:

16466

European-Finnish (FIN)

AF:

0.0107

AC:

AN:

280

Middle Eastern (MID)

AF:

0.000617

AC:

AN:

1620

European-Non Finnish (NFE)

AF:

0.00557

AC:

4248

AN:

762090

Other (OTH)

AF:

0.00305

AC:

AN:

27254

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

278

556

833

1111

1389

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

222

444

666

888

1110

<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:

0.00377

AC:

567

AN:

150546

Hom.:

Cov.:

AF XY:

0.00367

AC XY:

270

AN XY:

73622

show subpopulations

African (AFR)

AF:

0.00122

AC:

AN:

40256

American (AMR)

AF:

0.00105

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.000578

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0106

AC:

111

AN:

10482

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00560

AC:

380

AN:

67822

Other (OTH)

AF:

0.00191

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

118

148

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00427

Hom.:

Bravo

AF:

0.00297

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.43

PhyloP100

0.64

PromoterAI

0.087

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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