rs6196

chr5-143281925-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000176.3(NR3C1):c.2298T>C(p.Asn766=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 1,613,080 control chromosomes in the GnomAD database, including 19,890 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1921 hom., cov: 31)
  • Exomes 𝑓: 0.15 (17969 hom.)
• Consequence: NR3C1 NM_000176.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.67

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 5-143281925-A-G is Benign according to our data. Variant chr5-143281925-A-G is described in ClinVar as [Benign]. Clinvar id is 351364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-143281925-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.67 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR3C1	NM_000176.3	c.2298T>C	p.Asn766=	synonymous_variant	9/9	ENST00000394464.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR3C1	ENST00000394464.7	c.2298T>C	p.Asn766=	synonymous_variant	9/9	1	NM_000176.3	A1

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23036 AN: 152052 Hom.: 1917 Cov.: 31

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.242

Gnomad AMR AF: 0.0909

Gnomad ASJ AF: 0.0655

Gnomad EAS AF: 0.0725

Gnomad SAS AF: 0.0334

Gnomad FIN AF: 0.203

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.160

Gnomad OTH AF: 0.125

GnomAD3 exomes AF: 0.124 AC: 31150 AN: 250760 Hom.: 2496 AF XY: 0.121 AC XY: 16454 AN XY: 135596

Gnomad AFR exome AF: 0.178

Gnomad AMR exome AF: 0.0648

Gnomad ASJ exome AF: 0.0705

Gnomad EAS exome AF: 0.0709

Gnomad SAS exome AF: 0.0327

Gnomad FIN exome AF: 0.201

Gnomad NFE exome AF: 0.158

Gnomad OTH exome AF: 0.127

GnomAD4 exome AF: 0.150 AC: 219156 AN: 1460910 Hom.: 17969 Cov.: 31 AF XY: 0.146 AC XY: 105980 AN XY: 726802

Gnomad4 AFR exome AF: 0.177

Gnomad4 AMR exome AF: 0.0704

Gnomad4 ASJ exome AF: 0.0716

Gnomad4 EAS exome AF: 0.0705

Gnomad4 SAS exome AF: 0.0325

Gnomad4 FIN exome AF: 0.203

Gnomad4 NFE exome AF: 0.165

Gnomad4 OTH exome AF: 0.140

GnomAD4 genome AF: 0.152 AC: 23070 AN: 152170 Hom.: 1921 Cov.: 31 AF XY: 0.150 AC XY: 11138 AN XY: 74396

Gnomad4 AFR AF: 0.178

Gnomad4 AMR AF: 0.0908

Gnomad4 ASJ AF: 0.0655

Gnomad4 EAS AF: 0.0725

Gnomad4 SAS AF: 0.0324

Gnomad4 FIN AF: 0.203

Gnomad4 NFE AF: 0.160

Gnomad4 OTH AF: 0.124

Alfa AF: 0.147 Hom.: 3530

Bravo AF: 0.145

Asia WGS AF: 0.0740 AC: 258 AN: 3478

EpiCase AF: 0.145

EpiControl AF: 0.139

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glucocorticoid resistance Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	4.8
Dann	Benign	0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs6196; hg19: chr5-142661490; COSMIC: COSV51543216;