5-143400967-G-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001024094.2(NR3C1):​c.-13-115C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000154 in 649,076 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: NR3C1 NM_001024094.2 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001024094.2. 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>A		intron	N/A	NP_000167.1
	NR3C1	NM_001024094.2		c.-13-115C>A		intron	N/A	NP_001019265.1
	NR3C1	NM_001364183.2		c.-13-115C>A		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>A		intron	N/A	ENSP00000377977.2
	NR3C1	ENST00000231509.7	TSL:1	c.-13-115C>A		intron	N/A	ENSP00000231509.3
	NR3C1	ENST00000504572.5	TSL:1	c.-13-115C>A		intron	N/A	ENSP00000422518.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000154 AC: 1 AN: 649076 Hom.: 0 AF XY: 0.00000290 AC XY: 1 AN XY: 345358

African (AFR) AF: 0.00 AC: 0 AN: 17248

American (AMR) AF: 0.00 AC: 0 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: 0.00 AC: 0 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: 0.00000243 AC: 1 AN: 411676

Other (OTH) AF: 0.00 AC: 0 AN: 33704

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	10
DANN	Benign	0.78
PhyloP100		-0.046
PromoterAI		-0.027	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;