5-143416967-A-G

Variant names:

• chr5-143416967-A-G
• rs4607376
• ENST00000504572.5:c.-13-16115T>C

Variant summary

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

The ENST00000504572.5(NR3C1):​c.-13-16115T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.432 in 151,932 control chromosomes in the GnomAD database, including 15,429 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 0.43 (15429 hom., cov: 32)
• Consequence: NR3C1 ENST00000504572.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.16
• Publications: 22 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

ENSG00000305502 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.517 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR3C1	NM_001364183.2	c.-13-16115T>C		intron_variant	Intron 2 of 9		NP_001351112.1
NR3C1	NM_001018074.1	c.-13-16115T>C		intron_variant	Intron 1 of 8		NP_001018084.1
NR3C1	NM_001018075.1	c.-13-16115T>C		intron_variant	Intron 1 of 8		NP_001018085.1
NR3C1	NM_001018077.1	c.-13-16115T>C		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.-13-16115T>C		intron_variant	Intron 2 of 9	1		ENSP00000422518.1
NR3C1	ENST00000343796.6	c.-13-16115T>C		intron_variant	Intron 1 of 8	5		ENSP00000343205.2
NR3C1	ENST00000503701.1	n.353-7728T>C		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.432 AC: 65635 AN: 151812 Hom.: 15429 Cov.: 32

Gnomad AFR AF: 0.236

Gnomad AMI AF: 0.564

Gnomad AMR AF: 0.437

Gnomad ASJ AF: 0.462

Gnomad EAS AF: 0.532

Gnomad SAS AF: 0.368

Gnomad FIN AF: 0.577

Gnomad MID AF: 0.379

Gnomad NFE AF: 0.521

Gnomad OTH AF: 0.455

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

GnomAD4 genome AF: 0.432 AC: 65657 AN: 151932 Hom.: 15429 Cov.: 32 AF XY: 0.436 AC XY: 32382 AN XY: 74304

African (AFR) AF: 0.236 AC: 9788 AN: 41434

American (AMR) AF: 0.437 AC: 6665 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 1603 AN: 3468

East Asian (EAS) AF: 0.531 AC: 2744 AN: 5166

South Asian (SAS) AF: 0.369 AC: 1779 AN: 4826

European-Finnish (FIN) AF: 0.577 AC: 6086 AN: 10554

Middle Eastern (MID) AF: 0.380 AC: 111 AN: 292

European-Non Finnish (NFE) AF: 0.521 AC: 35408 AN: 67914

Other (OTH) AF: 0.455 AC: 959 AN: 2110

Alfa AF: 0.483 Hom.: 57632

Bravo AF: 0.415

Asia WGS AF: 0.449 AC: 1560 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.1
DANN	Benign	0.67
PhyloP100		1.2
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: rs4607376; hg19: chr5-142796532; COSMIC: COSV59431093;