chr5-143281479-AG-A

Variant names:

• chr5-143281479-AG-A
• rs10482707
• NM_000176.3:c.*409delC

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_000176.3(NR3C1):​c.*409delC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000999 in 212,218 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00084 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (1 hom.)
• Consequence: NR3C1 NM_000176.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.22
• Publications: 1 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

ENSG00000300303 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000837 (126/150586) while in subpopulation AFR AF = 0.00283 (114/40326). AF 95% confidence interval is 0.00241. There are 1 homozygotes in GnomAd4. There are 58 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 126 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.*409delC		3_prime_UTR	Exon 9 of 9	NP_000167.1
	NR3C1	NR_157096.2		n.1666delC		non_coding_transcript_exon	Exon 8 of 8
	NR3C1	NM_001024094.2		c.*409delC		3_prime_UTR	Exon 9 of 9	NP_001019265.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C1	ENST00000394464.7	TSL:1 MANE Select	c.*409delC		3_prime_UTR	Exon 9 of 9	ENSP00000377977.2
	NR3C1	ENST00000231509.7	TSL:1	c.*409delC		3_prime_UTR	Exon 9 of 9	ENSP00000231509.3
	NR3C1	ENST00000504572.5	TSL:1	c.*409delC		3_prime_UTR	Exon 10 of 10	ENSP00000422518.1

Frequencies

GnomAD3 genomes AF: 0.000837 AC: 126 AN: 150472 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00284

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000948

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00140 AC: 86 AN: 61632 Hom.: 1 Cov.: 0 AF XY: 0.00136 AC XY: 44 AN XY: 32334

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00726 AC: 7 AN: 964

American (AMR) AF: 0.000842 AC: 3 AN: 3562

Ashkenazi Jewish (ASJ) AF: 0.00146 AC: 2 AN: 1370

East Asian (EAS) AF: 0.00198 AC: 6 AN: 3024

South Asian (SAS) AF: 0.00178 AC: 16 AN: 8966

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 196

European-Non Finnish (NFE) AF: 0.00132 AC: 49 AN: 37136

Other (OTH) AF: 0.000961 AC: 3 AN: 3122

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000837 AC: 126 AN: 150586 Hom.: 1 Cov.: 31 AF XY: 0.000788 AC XY: 58 AN XY: 73606

African (AFR) AF: 0.00283 AC: 114 AN: 40326

American (AMR) AF: 0.000132 AC: 2 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4784

European-Finnish (FIN) AF: 0.0000948 AC: 1 AN: 10552

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67816

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000990

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Glucocorticoid resistance Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs10482707; hg19: chr5-142661044;