5-143311031-T-C

Variant names:

• chr5-143311031-T-C
• rs852978
• NM_000176.3:c.1352-818A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000176.3(NR3C1):​c.1352-818A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 152,200 control chromosomes in the GnomAD database, including 1,862 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 0.15 (1862 hom., cov: 32)
• Consequence: NR3C1 NM_000176.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.728
• Publications: 5 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

ENSG00000300303 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR3C1	NM_000176.3	c.1352-818A>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.1352-818A>G		intron_variant	Intron 3 of 8	1	NM_000176.3	ENSP00000377977.2

Frequencies

GnomAD3 genomes AF: 0.149 AC: 22611 AN: 152082 Hom.: 1858 Cov.: 32

Gnomad AFR AF: 0.177

Gnomad AMI AF: 0.244

Gnomad AMR AF: 0.0826

Gnomad ASJ AF: 0.0614

Gnomad EAS AF: 0.0724

Gnomad SAS AF: 0.0339

Gnomad FIN AF: 0.203

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.121

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.149 AC: 22645 AN: 152200 Hom.: 1862 Cov.: 32 AF XY: 0.147 AC XY: 10934 AN XY: 74412

African (AFR) AF: 0.177 AC: 7364 AN: 41508

American (AMR) AF: 0.0825 AC: 1263 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0614 AC: 213 AN: 3470

East Asian (EAS) AF: 0.0724 AC: 375 AN: 5182

South Asian (SAS) AF: 0.0329 AC: 159 AN: 4828

European-Finnish (FIN) AF: 0.203 AC: 2144 AN: 10586

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.157 AC: 10646 AN: 68010

Other (OTH) AF: 0.120 AC: 254 AN: 2114

Alfa AF: 0.128 Hom.: 606

Bravo AF: 0.142

Asia WGS AF: 0.0740 AC: 257 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.18
DANN	Benign	0.57
PhyloP100		-0.73
Mutation Taster		=100/0	polymorphism (auto)

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: rs852978; hg19: chr5-142690596;