5-143281479-AG-AGG

Variant names:

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

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.*409dupC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00384 in 212,378 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0047 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0017 (0 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 = 0.00471 (709/150586) while in subpopulation AFR AF = 0.0145 (586/40324). AF 95% confidence interval is 0.0136. There are 2 homozygotes in GnomAd4. There are 347 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 709 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR3C1	NM_000176.3	c.*409dupC		3_prime_UTR_variant	Exon 9 of 9	ENST00000394464.7	NP_000167.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR3C1	ENST00000394464.7	c.*409dupC		3_prime_UTR_variant	Exon 9 of 9	1	NM_000176.3	ENSP00000377977.2

Frequencies

GnomAD3 genomes AF: 0.00473 AC: 711 AN: 150472 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.0146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00461

Gnomad ASJ AF: 0.000290

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000413

Gnomad OTH AF: 0.00242

GnomAD4 exome AF: 0.00173 AC: 107 AN: 61792 Hom.: 0 Cov.: 0 AF XY: 0.00204 AC XY: 66 AN XY: 32430

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

African (AFR) AF: 0.0155 AC: 15 AN: 966

American (AMR) AF: 0.00812 AC: 29 AN: 3570

Ashkenazi Jewish (ASJ) AF: 0.000728 AC: 1 AN: 1374

East Asian (EAS) AF: 0.00 AC: 0 AN: 3028

South Asian (SAS) AF: 0.000556 AC: 5 AN: 8992

European-Finnish (FIN) AF: 0.0117 AC: 38 AN: 3248

Middle Eastern (MID) AF: 0.00510 AC: 1 AN: 196

European-Non Finnish (NFE) AF: 0.000349 AC: 13 AN: 37276

Other (OTH) AF: 0.00159 AC: 5 AN: 3142

⚠️ 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: 0.00471 AC: 709 AN: 150586 Hom.: 2 Cov.: 31 AF XY: 0.00471 AC XY: 347 AN XY: 73606

African (AFR) AF: 0.0145 AC: 586 AN: 40324

American (AMR) AF: 0.00467 AC: 71 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.000290 AC: 1 AN: 3454

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5164

South Asian (SAS) AF: 0.000836 AC: 4 AN: 4784

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10552

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000413 AC: 28 AN: 67816

Other (OTH) AF: 0.00239 AC: 5 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00535

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism

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;