5-143399752-T-C

Variant names:

• chr5-143399752-T-C
• rs56149945
• NM_000176.3:c.1088A>G

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.1088A>G​(p.Asn363Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0271 in 1,614,126 control chromosomes in the GnomAD database, including 696 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (41 hom., cov: 32)
  • Exomes 𝑓: 0.028 (655 hom.)
• Consequence: NR3C1 NM_000176.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.831
• Publications: 380 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=0.007912159).
• BP6: Variant 5-143399752-T-C is Benign according to our data. Variant chr5-143399752-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 16150.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 = 0.0191 (2915/152276) while in subpopulation NFE AF = 0.033 (2243/68024). AF 95% confidence interval is 0.0318. There are 41 homozygotes in GnomAd4. There are 1348 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2915 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.1088A>G	p.Asn363Ser	missense	Exon 2 of 9	NP_000167.1	P04150-1
	NR3C1	NM_001024094.2		c.1088A>G	p.Asn363Ser	missense	Exon 2 of 9	NP_001019265.1	E5KQF6
	NR3C1	NM_001364183.2		c.1088A>G	p.Asn363Ser	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.1088A>G	p.Asn363Ser	missense	Exon 2 of 9	ENSP00000377977.2	P04150-1
	NR3C1	ENST00000231509.7	TSL:1	c.1088A>G	p.Asn363Ser	missense	Exon 2 of 9	ENSP00000231509.3	P04150-3
	NR3C1	ENST00000504572.5	TSL:1	c.1088A>G	p.Asn363Ser	missense	Exon 3 of 10	ENSP00000422518.1	P04150-3

Frequencies

GnomAD3 genomes AF: 0.0192 AC: 2915 AN: 152158 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.00521

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.0191

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0330

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.0197 AC: 4944 AN: 251480 AF XY: 0.0199

Gnomad AFR exome AF: 0.00498

Gnomad AMR exome AF: 0.00948

Gnomad ASJ exome AF: 0.00665

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0175

Gnomad NFE exome AF: 0.0331

Gnomad OTH exome AF: 0.0200

GnomAD4 exome AF: 0.0279 AC: 40773 AN: 1461850 Hom.: 655 Cov.: 32 AF XY: 0.0277 AC XY: 20165 AN XY: 727232

African (AFR) AF: 0.00421 AC: 141 AN: 33480

American (AMR) AF: 0.0103 AC: 460 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00574 AC: 150 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00748 AC: 645 AN: 86258

European-Finnish (FIN) AF: 0.0183 AC: 975 AN: 53420

Middle Eastern (MID) AF: 0.00451 AC: 26 AN: 5768

European-Non Finnish (NFE) AF: 0.0334 AC: 37148 AN: 1111974

Other (OTH) AF: 0.0203 AC: 1227 AN: 60394

GnomAD4 genome AF: 0.0191 AC: 2915 AN: 152276 Hom.: 41 Cov.: 32 AF XY: 0.0181 AC XY: 1348 AN XY: 74446

African (AFR) AF: 0.00520 AC: 216 AN: 41556

American (AMR) AF: 0.0111 AC: 170 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00692 AC: 24 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4828

European-Finnish (FIN) AF: 0.0191 AC: 202 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0330 AC: 2243 AN: 68024

Other (OTH) AF: 0.0161 AC: 34 AN: 2106

Alfa AF: 0.0278 Hom.: 125

Bravo AF: 0.0180

TwinsUK AF: 0.0302 AC: 112

ALSPAC AF: 0.0348 AC: 134

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.0306 AC: 263

ExAC AF: 0.0208 AC: 2520

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0278

EpiControl AF: 0.0274

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 POLYMORPHISM (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	14
DANN	Benign	0.72
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0079	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.83
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.090	N
REVEL	Benign	0.052
Sift	Benign	0.69	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.046
MPC		0.047
ClinPred		0.0013	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.031
gMVP		0.18
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: rs56149945; hg19: chr5-142779317;