5-143429077-T-A

Variant names:

• chr5-143429077-T-A
• rs17100289
• ENST00000504572.5:c.-14+4642A>T

Variant summary

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

The ENST00000504572.5(NR3C1):​c.-14+4642A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.562 in 152,116 control chromosomes in the GnomAD database, including 25,399 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 0.56 (25399 hom., cov: 32)
• Consequence: NR3C1 ENST00000504572.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.283
• Publications: 8 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=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.66 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR3C1	NM_001364183.2	c.-14+4642A>T		intron_variant	Intron 2 of 9		NP_001351112.1
NR3C1	NM_001018074.1	c.-14+6127A>T		intron_variant	Intron 1 of 8		NP_001018084.1
NR3C1	NM_001018075.1	c.-14+6224A>T		intron_variant	Intron 1 of 8		NP_001018085.1
NR3C1	NM_001018077.1	c.-14+5455A>T		intron_variant	Intron 1 of 8		NP_001018087.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR3C1	ENST00000504572.5	c.-14+4642A>T		intron_variant	Intron 2 of 9	1		ENSP00000422518.1
NR3C1	ENST00000343796.6	c.-14+5455A>T		intron_variant	Intron 1 of 8	5		ENSP00000343205.2
NR3C1	ENST00000503701.1	n.352+4642A>T		intron_variant	Intron 2 of 2	3
NR3C1	ENST00000505058.5	n.241+5455A>T		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.563 AC: 85513 AN: 152000 Hom.: 25404 Cov.: 32

Gnomad AFR AF: 0.356

Gnomad AMI AF: 0.632

Gnomad AMR AF: 0.573

Gnomad ASJ AF: 0.730

Gnomad EAS AF: 0.560

Gnomad SAS AF: 0.577

Gnomad FIN AF: 0.625

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.665

Gnomad OTH AF: 0.582

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

GnomAD4 genome AF: 0.562 AC: 85532 AN: 152116 Hom.: 25399 Cov.: 32 AF XY: 0.562 AC XY: 41749 AN XY: 74350

African (AFR) AF: 0.356 AC: 14763 AN: 41490

American (AMR) AF: 0.573 AC: 8758 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.730 AC: 2531 AN: 3468

East Asian (EAS) AF: 0.560 AC: 2896 AN: 5172

South Asian (SAS) AF: 0.578 AC: 2783 AN: 4818

European-Finnish (FIN) AF: 0.625 AC: 6614 AN: 10580

Middle Eastern (MID) AF: 0.595 AC: 175 AN: 294

European-Non Finnish (NFE) AF: 0.665 AC: 45199 AN: 67988

Other (OTH) AF: 0.585 AC: 1237 AN: 2114

Alfa AF: 0.605 Hom.: 3592

Bravo AF: 0.548

Asia WGS AF: 0.544 AC: 1894 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.38
DANN	Benign	0.34
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs17100289; hg19: chr5-142808642; COSMIC: COSV59429845;