5-143405182-C-G

Variant names:

• chr5-143405182-C-G
• rs35722527
• ENST00000514699.1:c.-46G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0660
• Publications: 4 publications found

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

LOC128966704 (HGNC:):

ACMG classification

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	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR3C1	NM_001364180.2	c.-46G>C		5_prime_UTR_variant	Exon 1 of 9		NP_001351109.1
NR3C1	NM_001364183.2	c.-13-4330G>C		intron_variant	Intron 2 of 9		NP_001351112.1
NR3C1	NM_001018074.1	c.-13-4330G>C		intron_variant	Intron 1 of 8		NP_001018084.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00503 AC: 765 AN: 152210 Hom.: 4 Cov.: 31

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.: 4 Cov.: 29 AF XY: 0.000494 AC XY: 190 AN XY: 384832

African (AFR) AF: 0.0189 AC: 298 AN: 15786

American (AMR) AF: 0.00102 AC: 1 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5154

East Asian (EAS) AF: 0.00 AC: 0 AN: 3636

South Asian (SAS) AF: 0.00 AC: 0 AN: 16460

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 278

Middle Eastern (MID) AF: 0.00123 AC: 2 AN: 1622

European-Non Finnish (NFE) AF: 0.000114 AC: 87 AN: 762040

Other (OTH) AF: 0.00103 AC: 28 AN: 27304

GnomAD4 genome AF: 0.00504 AC: 768 AN: 152328 Hom.: 4 Cov.: 31 AF XY: 0.00483 AC XY: 360 AN XY: 74482

African (AFR) AF: 0.0172 AC: 716 AN: 41574

American (AMR) AF: 0.00209 AC: 32 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68030

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00515 Hom.: 0

Bravo AF: 0.00557

Asia WGS AF: 0.00115 AC: 5 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	15
DANN	Benign	0.88
PhyloP100		-0.066
PromoterAI		-0.0054	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35722527; hg19: chr5-142784747;