5-143413085-A-G

Variant names:

• chr5-143413085-A-G
• rs7701443
• ENST00000504572.5:c.-13-12233T>C

Variant summary

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

The ENST00000504572.5(NR3C1):​c.-13-12233T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.434 in 152,046 control chromosomes in the GnomAD database, including 14,514 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 (14514 hom., cov: 32)
• Consequence: NR3C1 ENST00000504572.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.272
• Publications: 36 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=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.587 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR3C1	NM_001364183.2	c.-13-12233T>C		intron_variant	Intron 2 of 9		NP_001351112.1
NR3C1	NM_001018074.1	c.-13-12233T>C		intron_variant	Intron 1 of 8		NP_001018084.1
NR3C1	NM_001018075.1	c.-13-12233T>C		intron_variant	Intron 1 of 8		NP_001018085.1
NR3C1	NM_001018077.1	c.-13-12233T>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.-13-12233T>C		intron_variant	Intron 2 of 9	1		ENSP00000422518.1
NR3C1	ENST00000343796.6	c.-13-12233T>C		intron_variant	Intron 1 of 8	5		ENSP00000343205.2
NR3C1	ENST00000503701.1	n.353-3846T>C		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.434 AC: 65922 AN: 151928 Hom.: 14514 Cov.: 32

Gnomad AFR AF: 0.468

Gnomad AMI AF: 0.339

Gnomad AMR AF: 0.450

Gnomad ASJ AF: 0.465

Gnomad EAS AF: 0.605

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.391

Gnomad MID AF: 0.376

Gnomad NFE AF: 0.405

Gnomad OTH AF: 0.425

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

GnomAD4 genome AF: 0.434 AC: 65952 AN: 152046 Hom.: 14514 Cov.: 32 AF XY: 0.436 AC XY: 32404 AN XY: 74328

African (AFR) AF: 0.468 AC: 19394 AN: 41462

American (AMR) AF: 0.450 AC: 6878 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.465 AC: 1615 AN: 3472

East Asian (EAS) AF: 0.605 AC: 3128 AN: 5172

South Asian (SAS) AF: 0.412 AC: 1987 AN: 4818

European-Finnish (FIN) AF: 0.391 AC: 4136 AN: 10576

Middle Eastern (MID) AF: 0.373 AC: 109 AN: 292

European-Non Finnish (NFE) AF: 0.405 AC: 27504 AN: 67954

Other (OTH) AF: 0.424 AC: 892 AN: 2106

Alfa AF: 0.420 Hom.: 24842

Bravo AF: 0.443

Asia WGS AF: 0.478 AC: 1661 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.8
DANN	Benign	0.65
PhyloP100		0.27
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: rs7701443; hg19: chr5-142792650;