5-143313891-T-C

Variant names:

• chr5-143313891-T-C
• rs10482667
• NM_000176.3:c.1351+111A>G

Variant summary

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

The NM_000176.3(NR3C1):​c.1351+111A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0178 in 1,155,904 control chromosomes in the GnomAD database, including 330 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 0.016 (44 hom., cov: 32)
  • Exomes 𝑓: 0.018 (286 hom.)
• Consequence: NR3C1 NM_000176.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.153
• Publications: 0 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0157 (2396/152318) while in subpopulation NFE AF = 0.0203 (1379/68020). AF 95% confidence interval is 0.0194. There are 44 homozygotes in GnomAd4. There are 1258 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2396 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR3C1	NM_000176.3	c.1351+111A>G		intron_variant	Intron 3 of 8	ENST00000394464.7	NP_000167.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR3C1	ENST00000394464.7	c.1351+111A>G		intron_variant	Intron 3 of 8	1	NM_000176.3	ENSP00000377977.2

Frequencies

GnomAD3 genomes AF: 0.0157 AC: 2396 AN: 152200 Hom.: 44 Cov.: 32

Gnomad AFR AF: 0.00299

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.0702

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0203

Gnomad OTH AF: 0.00716

GnomAD4 exome AF: 0.0181 AC: 18125 AN: 1003586 Hom.: 286 AF XY: 0.0176 AC XY: 9126 AN XY: 517498

African (AFR) AF: 0.00267 AC: 63 AN: 23598

American (AMR) AF: 0.00259 AC: 108 AN: 41778

Ashkenazi Jewish (ASJ) AF: 0.0124 AC: 284 AN: 22890

East Asian (EAS) AF: 0.00 AC: 0 AN: 35742

South Asian (SAS) AF: 0.00691 AC: 516 AN: 74636

European-Finnish (FIN) AF: 0.0697 AC: 3499 AN: 50218

Middle Eastern (MID) AF: 0.00277 AC: 9 AN: 3252

European-Non Finnish (NFE) AF: 0.0184 AC: 12990 AN: 706514

Other (OTH) AF: 0.0146 AC: 656 AN: 44958

GnomAD4 genome AF: 0.0157 AC: 2396 AN: 152318 Hom.: 44 Cov.: 32 AF XY: 0.0169 AC XY: 1258 AN XY: 74482

African (AFR) AF: 0.00298 AC: 124 AN: 41582

American (AMR) AF: 0.00405 AC: 62 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0124 AC: 43 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00559 AC: 27 AN: 4826

European-Finnish (FIN) AF: 0.0702 AC: 745 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0203 AC: 1379 AN: 68020

Other (OTH) AF: 0.00709 AC: 15 AN: 2116

Alfa AF: 0.0191 Hom.: 59

Bravo AF: 0.0101

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.2
DANN	Benign	0.50
PhyloP100		-0.15
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs10482667; hg19: chr5-142693456;