Genetic Variant ENST00000514699.1:c.-46G>C (chr5-143405182-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The ENST00000514699.1(NR3C1):c.-46G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 985,592 control chromosomes in the GnomAD database, including 8 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 0.0050 ( 4 hom., cov: 31)

Exomes 𝑓: 0.00050 ( 4 hom. )

Consequence

NR3C1
ENST00000514699.1 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0660

Publications

4 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:

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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=-0.52).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00504 (768/152328) while in subpopulation AFR AF = 0.0172 (716/41574). AF 95% confidence interval is 0.0162. There are 4 homozygotes in GnomAd4. There are 360 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 768 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein	UniProt
NR3C1	NM_001364180.2 link	c.-46G>C	5_prime_UTR_variant	Exon 1 of 9	NP_001351109.1
NR3C1	NM_001364183.2 link	c.-13-4330G>C	intron_variant	Intron 2 of 9	NP_001351112.1
NR3C1	NM_001018074.1 link	c.-13-4330G>C	intron_variant	Intron 1 of 8	NP_001018084.1	P04150-1F1D8N4

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
NR3C1	ENST00000514699.1 link	c.-46G>C	5_prime_UTR_variant	Exon 1 of 2	1	ENSP00000426478.1	Q3MSN4
NR3C1	ENST00000504572.5 link	c.-13-4330G>C	intron_variant	Intron 2 of 9	1	ENSP00000422518.1	P04150-3
NR3C1	ENST00000343796.6 link	c.-13-4330G>C	intron_variant	Intron 1 of 8	5	ENSP00000343205.2	P04150-1

Frequencies

GnomAD3 genomes

AF:

0.00503

AC:

765

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0172

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00209

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00431

GnomAD4 exome

AF:

0.000499

AC:

416

AN:

833264

Hom.:

Cov.:

AF XY:

0.000494

AC XY:

190

AN XY:

384832

show subpopulations

African (AFR)

AF:

0.0189

AC:

298

AN:

15786

American (AMR)

AF:

0.00102

AC:

AN:

984

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5154

East Asian (EAS)

AF:

0.00

AC:

AN:

3636

South Asian (SAS)

AF:

0.00

AC:

AN:

16460

European-Finnish (FIN)

AF:

0.00

AC:

AN:

278

Middle Eastern (MID)

AF:

0.00123

AC:

AN:

1622

European-Non Finnish (NFE)

AF:

0.000114

AC:

AN:

762040

Other (OTH)

AF:

0.00103

AC:

AN:

27304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

116

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00504

AC:

768

AN:

152328

Hom.:

Cov.:

AF XY:

0.00483

AC XY:

360

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0172

AC:

716

AN:

41574

American (AMR)

AF:

0.00209

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68030

Other (OTH)

AF:

0.00426

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

121

162

202

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:

0.00515

Hom.:

Bravo

AF:

0.00557

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.88

PhyloP100

-0.066

PromoterAI

-0.0054

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over