ENST00000504572.5:c.-13-5488A>G

Variant names:

• chr5-143406340-T-C
• rs72801094
• ENST00000504572.5:c.-13-5488A>G

Variant summary

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

The ENST00000504572.5(NR3C1):​c.-13-5488A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.03 in 151,590 control chromosomes in the GnomAD database, including 111 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 0.030 (111 hom., cov: 31)
• Consequence: NR3C1 ENST00000504572.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.498
• 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

LOC128966704 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.03 (4553/151590) while in subpopulation NFE AF = 0.042 (2849/67894). AF 95% confidence interval is 0.0407. There are 111 homozygotes in GnomAd4. There are 2350 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4553 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC128966704	XM_054328421.1	c.-699A>G		5_prime_UTR_variant	Exon 1 of 2		XP_054184396.1
NR3C1	NM_001364183.2	c.-13-5488A>G		intron_variant	Intron 2 of 9		NP_001351112.1
NR3C1	NM_001018074.1	c.-13-5488A>G		intron_variant	Intron 1 of 8		NP_001018084.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR3C1	ENST00000504572.5	c.-13-5488A>G		intron_variant	Intron 2 of 9	1		ENSP00000422518.1
NR3C1	ENST00000343796.6	c.-13-5488A>G		intron_variant	Intron 1 of 8	5		ENSP00000343205.2
ENSG00000305502	ENST00000811340.1	n.557+319T>C		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.0301 AC: 4552 AN: 151476 Hom.: 111 Cov.: 31

Gnomad AFR AF: 0.00659

Gnomad AMI AF: 0.0551

Gnomad AMR AF: 0.0209

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.0941

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0419

Gnomad OTH AF: 0.0270

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

GnomAD4 genome AF: 0.0300 AC: 4553 AN: 151590 Hom.: 111 Cov.: 31 AF XY: 0.0317 AC XY: 2350 AN XY: 74102

African (AFR) AF: 0.00657 AC: 272 AN: 41374

American (AMR) AF: 0.0208 AC: 317 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3464

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00540 AC: 26 AN: 4818

European-Finnish (FIN) AF: 0.0941 AC: 969 AN: 10294

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0420 AC: 2849 AN: 67894

Other (OTH) AF: 0.0267 AC: 56 AN: 2096

Alfa AF: 0.0395 Hom.: 15

Bravo AF: 0.0244

Asia WGS AF: 0.00376 AC: 13 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.57
DANN	Benign	0.36
PhyloP100		-0.50
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs72801094; hg19: chr5-142785905;