chr5-143400772-C-T

Variant names:

• chr5-143400772-C-T
• rs6190
• NM_000176.3:c.68G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000176.3(NR3C1):​c.68G>A​(p.Arg23Lys) variant causes a missense change. The variant allele was found at a frequency of 0.024 in 1,614,144 control chromosomes in the GnomAD database, including 590 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.017 (42 hom., cov: 32)
  • Exomes 𝑓: 0.025 (548 hom.)
• Consequence: NR3C1 NM_000176.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.77
• Publications: 149 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039635897).
• BP6: Variant 5-143400772-C-T is Benign according to our data. Variant chr5-143400772-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 351377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0166 (2535/152312) while in subpopulation NFE AF = 0.0274 (1863/68038). AF 95% confidence interval is 0.0263. There are 42 homozygotes in GnomAd4. There are 1168 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2535 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.68G>A	p.Arg23Lys	missense	Exon 2 of 9	NP_000167.1	P04150-1
	NR3C1	NM_001024094.2		c.68G>A	p.Arg23Lys	missense	Exon 2 of 9	NP_001019265.1	E5KQF6
	NR3C1	NM_001364183.2		c.68G>A	p.Arg23Lys	missense	Exon 3 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.68G>A	p.Arg23Lys	missense	Exon 2 of 9	ENSP00000377977.2	P04150-1
	NR3C1	ENST00000231509.7	TSL:1	c.68G>A	p.Arg23Lys	missense	Exon 2 of 9	ENSP00000231509.3	P04150-3
	NR3C1	ENST00000504572.5	TSL:1	c.68G>A	p.Arg23Lys	missense	Exon 3 of 10	ENSP00000422518.1	P04150-3

Frequencies

GnomAD3 genomes AF: 0.0166 AC: 2533 AN: 152194 Hom.: 42 Cov.: 32

Gnomad AFR AF: 0.00456

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00621

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.0208

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0274

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.0183 AC: 4603 AN: 251468 AF XY: 0.0191

Gnomad AFR exome AF: 0.00443

Gnomad AMR exome AF: 0.00676

Gnomad ASJ exome AF: 0.0200

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0243

Gnomad NFE exome AF: 0.0263

Gnomad OTH exome AF: 0.0181

GnomAD4 exome AF: 0.0248 AC: 36197 AN: 1461832 Hom.: 548 Cov.: 32 AF XY: 0.0245 AC XY: 17834 AN XY: 727218

African (AFR) AF: 0.00355 AC: 119 AN: 33478

American (AMR) AF: 0.00720 AC: 322 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0195 AC: 510 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0152 AC: 1308 AN: 86256

European-Finnish (FIN) AF: 0.0223 AC: 1192 AN: 53404

Middle Eastern (MID) AF: 0.0158 AC: 91 AN: 5768

European-Non Finnish (NFE) AF: 0.0283 AC: 31434 AN: 1111974

Other (OTH) AF: 0.0202 AC: 1221 AN: 60392

GnomAD4 genome AF: 0.0166 AC: 2535 AN: 152312 Hom.: 42 Cov.: 32 AF XY: 0.0157 AC XY: 1168 AN XY: 74478

African (AFR) AF: 0.00455 AC: 189 AN: 41552

American (AMR) AF: 0.00621 AC: 95 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0184 AC: 64 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.0143 AC: 69 AN: 4824

European-Finnish (FIN) AF: 0.0208 AC: 221 AN: 10610

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0274 AC: 1863 AN: 68038

Other (OTH) AF: 0.0123 AC: 26 AN: 2116

Alfa AF: 0.0225 Hom.: 211

Bravo AF: 0.0149

TwinsUK AF: 0.0270 AC: 100

ALSPAC AF: 0.0304 AC: 117

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.0285 AC: 245

ExAC AF: 0.0178 AC: 2165

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.0253

EpiControl AF: 0.0254

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Glucocorticoid resistance (1)
-	-	1	NR3C1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.31	T
Eigen	Benign	0.044
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.8
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.14
Sift	Benign	0.035	D
Sift4G	Benign	0.98	T
Polyphen		0.29	B
Vest4		0.14
MPC		0.055
ClinPred		0.018	T
GERP RS		5.2
PromoterAI		0.014	Neutral
Varity_R		0.18
gMVP		0.22
Mutation Taster		=99/1	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: rs6190; hg19: chr5-142780337; COSMIC: COSV99039780;