5-143279701-T-C

Variant names:

• chr5-143279701-T-C
• rs6193
• NM_000176.3:c.*2188A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000176.3(NR3C1):​c.*2188A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00811 in 298,728 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (62 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (8 hom.)
• Consequence: NR3C1 NM_000176.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.05
• Publications: 3 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)

ENSG00000300303 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 5-143279701-T-C is Benign according to our data. Variant chr5-143279701-T-C is described in ClinVar as Benign. ClinVar VariationId is 351331.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0142 (2165/152270) while in subpopulation AFR AF = 0.0494 (2054/41542). AF 95% confidence interval is 0.0477. There are 62 homozygotes in GnomAd4. There are 1013 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2165 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C1	NM_000176.3	MANE Select	c.*2188A>G		3_prime_UTR	Exon 9 of 9	NP_000167.1	P04150-1
	NR3C1	NM_001024094.2		c.*2188A>G		3_prime_UTR	Exon 9 of 9	NP_001019265.1	E5KQF6
	NR3C1	NM_001364183.2		c.*2188A>G		3_prime_UTR	Exon 10 of 10	NP_001351112.1	P04150-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C1	ENST00000394464.7	TSL:1 MANE Select	c.*2188A>G		3_prime_UTR	Exon 9 of 9	ENSP00000377977.2	P04150-1
	NR3C1	ENST00000424646.6	TSL:1	c.*2188A>G		3_prime_UTR	Exon 9 of 9	ENSP00000405282.2	P04150-10
	NR3C1	ENST00000415690.6	TSL:1	c.2182-290A>G		intron	N/A	ENSP00000387672.2	P04150-2

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2167 AN: 152152 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.0496

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00485

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00861

GnomAD4 exome AF: 0.00176 AC: 258 AN: 146458 Hom.: 8 Cov.: 3 AF XY: 0.00161 AC XY: 122 AN XY: 75836

African (AFR) AF: 0.0492 AC: 182 AN: 3696

American (AMR) AF: 0.00347 AC: 11 AN: 3166

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5190

East Asian (EAS) AF: 0.00 AC: 0 AN: 7892

South Asian (SAS) AF: 0.000172 AC: 2 AN: 11650

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7836

Middle Eastern (MID) AF: 0.00129 AC: 1 AN: 778

European-Non Finnish (NFE) AF: 0.000197 AC: 19 AN: 96494

Other (OTH) AF: 0.00441 AC: 43 AN: 9756

GnomAD4 genome AF: 0.0142 AC: 2165 AN: 152270 Hom.: 62 Cov.: 32 AF XY: 0.0136 AC XY: 1013 AN XY: 74438

African (AFR) AF: 0.0494 AC: 2054 AN: 41542

American (AMR) AF: 0.00478 AC: 73 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68026

Other (OTH) AF: 0.00852 AC: 18 AN: 2112

Alfa AF: 0.00639 Hom.: 27

Bravo AF: 0.0157

Asia WGS AF: 0.00347 AC: 12 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Glucocorticoid resistance (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.6
DANN	Benign	0.71
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs6193; hg19: chr5-142659266;