chr5-143400967-G-A

Variant names:

• chr5-143400967-G-A
• rs10482620
• NM_000176.3:c.-13-115C>T

Variant summary

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

The NM_000176.3(NR3C1):​c.-13-115C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 801,294 control chromosomes in the GnomAD database, including 2 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 0.0040 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (1 hom.)
• Consequence: NR3C1 NM_000176.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0460
• Publications: 0 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=-0.78).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00398 (606/152218) while in subpopulation AFR AF = 0.0135 (561/41546). AF 95% confidence interval is 0.0126. There are 1 homozygotes in GnomAd4. There are 284 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 606 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000176.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C1	NM_000176.3	MANE Select	c.-13-115C>T		intron	N/A	NP_000167.1
	NR3C1	NM_001024094.2		c.-13-115C>T		intron	N/A	NP_001019265.1
	NR3C1	NM_001364183.2		c.-13-115C>T		intron	N/A	NP_001351112.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C1	ENST00000394464.7	TSL:1 MANE Select	c.-13-115C>T		intron	N/A	ENSP00000377977.2
	NR3C1	ENST00000231509.7	TSL:1	c.-13-115C>T		intron	N/A	ENSP00000231509.3
	NR3C1	ENST00000504572.5	TSL:1	c.-13-115C>T		intron	N/A	ENSP00000422518.1

Frequencies

GnomAD3 genomes AF: 0.00397 AC: 604 AN: 152100 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00335

GnomAD4 exome AF: 0.000532 AC: 345 AN: 649076 Hom.: 1 AF XY: 0.000460 AC XY: 159 AN XY: 345358

African (AFR) AF: 0.0125 AC: 215 AN: 17248

American (AMR) AF: 0.000882 AC: 30 AN: 34016

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20360

East Asian (EAS) AF: 0.00 AC: 0 AN: 32462

South Asian (SAS) AF: 0.0000631 AC: 4 AN: 63374

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2916

European-Non Finnish (NFE) AF: 0.000136 AC: 56 AN: 411676

Other (OTH) AF: 0.00119 AC: 40 AN: 33704

GnomAD4 genome AF: 0.00398 AC: 606 AN: 152218 Hom.: 1 Cov.: 32 AF XY: 0.00382 AC XY: 284 AN XY: 74414

African (AFR) AF: 0.0135 AC: 561 AN: 41546

American (AMR) AF: 0.00177 AC: 27 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68004

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00105 Hom.: 0

Bravo AF: 0.00448

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	13
DANN	Benign	0.86
PhyloP100		-0.046
PromoterAI		-0.017	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs10482620; hg19: chr5-142780532;