dbSNP rs10052957: NR3C1:c.-13-6284C>T (chr5-143407136-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000504572.5(NR3C1):c.-13-6284C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.281 in 152,140 control chromosomes in the GnomAD database, including 6,254 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 0.28 ( 6250 hom., cov: 32)

Exomes 𝑓: 0.30 ( 4 hom. )

Consequence

NR3C1
ENST00000504572.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.270

Publications

77 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:

LOC128966704 (HGNC:):

LOC128966704 links:

Genome browser will be placed here

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=-0.92).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.32 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein
LOC128966704	XM_054328421.1 link	c.-1495C>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 2	XP_054184396.1
LOC128966704	XM_054328421.1 link	c.-1495C>T	5_prime_UTR_variant	Exon 1 of 2	XP_054184396.1
NR3C1	NM_001364183.2 link	c.-13-6284C>T	intron_variant	Intron 2 of 9	NP_001351112.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
NR3C1	ENST00000504572.5 link	c.-13-6284C>T	intron_variant	Intron 2 of 9	1	ENSP00000422518.1	P04150-3
ENSG00000279130	ENST00000623204.1 link	n.178G>A	non_coding_transcript_exon_variant	Exon 1 of 1	6
NR3C1	ENST00000343796.6 link	c.-13-6284C>T	intron_variant	Intron 1 of 8	5	ENSP00000343205.2	P04150-1
ENSG00000305502	ENST00000811340.1 link	n.557+1115G>A	intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.281

AC:

42654

AN:

151968

Hom.:

6248

Cov.:

show subpopulations

Gnomad AFR

AF:

0.270

Gnomad AMI

AF:

0.331

Gnomad AMR

AF:

0.202

Gnomad ASJ

AF:

0.294

Gnomad EAS

AF:

0.0945

Gnomad SAS

AF:

0.193

Gnomad FIN

AF:

0.280

Gnomad MID

AF:

0.348

Gnomad NFE

AF:

0.324

Gnomad OTH

AF:

0.281

GnomAD4 exome

AF:

0.304

AC:

AN:

Hom.:

Cov.:

AF XY:

0.250

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.500

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.250

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.375

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.281

AC:

42685

AN:

152084

Hom.:

6250

Cov.:

AF XY:

0.275

AC XY:

20418

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.270

AC:

11204

AN:

41480

American (AMR)

AF:

0.202

AC:

3085

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.294

AC:

1018

AN:

3466

East Asian (EAS)

AF:

0.0946

AC:

490

AN:

5182

South Asian (SAS)

AF:

0.192

AC:

926

AN:

4822

European-Finnish (FIN)

AF:

0.280

AC:

2962

AN:

10578

Middle Eastern (MID)

AF:

0.347

AC:

102

AN:

294

European-Non Finnish (NFE)

AF:

0.324

AC:

22007

AN:

67952

Other (OTH)

AF:

0.279

AC:

589

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1592

3184

4776

6368

7960

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

436

872

1308

1744

2180

<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:

0.305

Hom.:

12066

Bravo

AF:

0.273

Asia WGS

AF:

0.166

AC:

579

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.34

(source)

DANN

Benign

0.30

PhyloP100

-0.27

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over