dbSNP rs10482609: NR3C1:c.-325T>G (chr5-143403522-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_000176.3(NR3C1):c.-325T>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00846 in 985,064 control chromosomes in the GnomAD database, including 74 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 0.010 ( 21 hom., cov: 33)

Exomes 𝑓: 0.0081 ( 53 hom. )

Consequence

NR3C1
NM_000176.3 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.328

Publications

2 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0104 (1575/151716) while in subpopulation SAS AF = 0.0363 (175/4820). AF 95% confidence interval is 0.0319. There are 21 homozygotes in GnomAd4. There are 832 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1575 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	Effect	Exon Rank	Protein	UniProt
NR3C1	NM_000176.3	MANE Select	c.-325T>G	5_prime_UTR	Exon 1 of 9	NP_000167.1	P04150-1
NR3C1	NM_001024094.2		c.-325T>G	5_prime_UTR	Exon 1 of 9	NP_001019265.1	E5KQF6
NR3C1	NM_001204258.2		c.-403T>G	5_prime_UTR	Exon 1 of 9	NP_001191187.1	P04150-8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NR3C1	ENST00000394464.7	TSL:1 MANE Select	c.-325T>G	5_prime_UTR	Exon 1 of 9	ENSP00000377977.2	P04150-1
NR3C1	ENST00000231509.7	TSL:1	c.-325T>G	5_prime_UTR	Exon 1 of 9	ENSP00000231509.3	P04150-3
NR3C1	ENST00000504572.5	TSL:1	c.-13-2670T>G	intron	N/A	ENSP00000422518.1	P04150-3

Frequencies

GnomAD3 genomes

AF:

0.0104

AC:

1572

AN:

151608

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00146

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0158

Gnomad ASJ

AF:

0.0649

Gnomad EAS

AF:

0.0220

Gnomad SAS

AF:

0.0361

Gnomad FIN

AF:

0.0128

Gnomad MID

AF:

0.0258

Gnomad NFE

AF:

0.00854

Gnomad OTH

AF:

0.0177

GnomAD4 exome

AF:

0.00811

AC:

6758

AN:

833348

Hom.:

Cov.:

AF XY:

0.00843

AC XY:

3246

AN XY:

384892

show subpopulations

African (AFR)

AF:

0.00146

AC:

AN:

15792

American (AMR)

AF:

0.00609

AC:

AN:

986

Ashkenazi Jewish (ASJ)

AF:

0.0623

AC:

321

AN:

5154

East Asian (EAS)

AF:

0.0253

AC:

AN:

3642

South Asian (SAS)

AF:

0.0371

AC:

611

AN:

16466

European-Finnish (FIN)

AF:

0.00694

AC:

AN:

288

Middle Eastern (MID)

AF:

0.0370

AC:

AN:

1622

European-Non Finnish (NFE)

AF:

0.00687

AC:

5236

AN:

762096

Other (OTH)

AF:

0.0149

AC:

407

AN:

27302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

417

833

1250

1666

2083

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

316

632

948

1264

1580

<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:

0.0104

AC:

1575

AN:

151716

Hom.:

Cov.:

AF XY:

0.0112

AC XY:

832

AN XY:

74142

show subpopulations

African (AFR)

AF:

0.00145

AC:

AN:

41354

American (AMR)

AF:

0.0158

AC:

241

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0649

AC:

225

AN:

3466

East Asian (EAS)

AF:

0.0221

AC:

112

AN:

5076

South Asian (SAS)

AF:

0.0363

AC:

175

AN:

4820

European-Finnish (FIN)

AF:

0.0128

AC:

135

AN:

10534

Middle Eastern (MID)

AF:

0.0278

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00854

AC:

580

AN:

67876

Other (OTH)

AF:

0.0185

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

150

226

301

376

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00873

Hom.:

Bravo

AF:

0.00997

Asia WGS

AF:

0.0450

AC:

155

AN:

3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.78

PhyloP100

0.33

PromoterAI

0.019

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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