5-143402837-C-T

Variant names:

• chr5-143402837-C-T
• rs10482614
• NM_000176.3:c.-14+374G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001364185.1(NR3C1):​c.-249G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 985,192 control chromosomes in the GnomAD database, including 12,785 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 0.15 (1847 hom., cov: 33)
  • Exomes 𝑓: 0.16 (10938 hom.)
• Consequence: NR3C1 NM_001364185.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.885
• Publications: 14 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: Orphanet, Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001364185.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C1	NM_000176.3	MANE Select	c.-14+374G>A		intron	N/A	NP_000167.1	P04150-1
	NR3C1	NM_001364185.1		c.-249G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	NP_001351114.1	P04150-3
	NR3C1	NM_001364182.1		c.-249G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	NP_001351111.1	P04150-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C1	ENST00000394464.7	TSL:1 MANE Select	c.-14+374G>A		intron	N/A	ENSP00000377977.2	P04150-1
	NR3C1	ENST00000231509.7	TSL:1	c.-14+374G>A		intron	N/A	ENSP00000231509.3	P04150-3
	NR3C1	ENST00000504572.5	TSL:1	c.-13-1985G>A		intron	N/A	ENSP00000422518.1	P04150-3

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22538 AN: 152114 Hom.: 1841 Cov.: 33

Gnomad AFR AF: 0.176

Gnomad AMI AF: 0.242

Gnomad AMR AF: 0.0822

Gnomad ASJ AF: 0.0695

Gnomad EAS AF: 0.0653

Gnomad SAS AF: 0.0343

Gnomad FIN AF: 0.202

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.123

GnomAD4 exome AF: 0.160 AC: 133434 AN: 832962 Hom.: 10938 Cov.: 29 AF XY: 0.160 AC XY: 61445 AN XY: 384662

African (AFR) AF: 0.177 AC: 2796 AN: 15786

American (AMR) AF: 0.0813 AC: 80 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.0687 AC: 354 AN: 5152

East Asian (EAS) AF: 0.0758 AC: 275 AN: 3630

South Asian (SAS) AF: 0.0335 AC: 551 AN: 16456

European-Finnish (FIN) AF: 0.209 AC: 58 AN: 278

Middle Eastern (MID) AF: 0.0327 AC: 53 AN: 1620

European-Non Finnish (NFE) AF: 0.165 AC: 125410 AN: 761768

Other (OTH) AF: 0.141 AC: 3857 AN: 27288

GnomAD4 genome AF: 0.148 AC: 22573 AN: 152230 Hom.: 1847 Cov.: 33 AF XY: 0.146 AC XY: 10878 AN XY: 74432

African (AFR) AF: 0.177 AC: 7338 AN: 41554

American (AMR) AF: 0.0821 AC: 1257 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0695 AC: 241 AN: 3470

East Asian (EAS) AF: 0.0653 AC: 337 AN: 5162

South Asian (SAS) AF: 0.0333 AC: 161 AN: 4834

European-Finnish (FIN) AF: 0.202 AC: 2147 AN: 10606

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.156 AC: 10607 AN: 67978

Other (OTH) AF: 0.121 AC: 257 AN: 2116

Alfa AF: 0.124 Hom.: 385

Bravo AF: 0.141

Asia WGS AF: 0.0700 AC: 245 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	4.1
DANN	Benign	0.96
PhyloP100		-0.89
PromoterAI		-0.11	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs10482614; hg19: chr5-142782402;