NM_000176.3:c.1088A>G

Variant names:

• chr5-143399752-T-C
• rs56149945
• NM_000176.3:c.1088A>G
• NR3C1 p.Asn363Ser

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-5 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -5 classification points (ACGS-UK Somatic Oncogenicity v2025). B1_StrongB3_Supporting

The NM_000176.3(NR3C1):c.1088A>G (p.Asn363Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene NR3C1 is a tumor suppressor gene (CancerMine: 5 TSG, 2 oncogene, 1 driver citations). The gene NR3C1 is a known oncogene (CancerMine: 5 TSG, 2 oncogene, 1 driver citations). The gene NR3C1 is a cancer driver gene (CancerMine: 5 TSG, 2 oncogene, 1 driver citations). The variant allele was found at a cumulative frequency of 0.0271 (AC=43,688) in the gnomAD database across 1,614,126 control chromosomes, including 696 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.0331. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★). The variant has been observed in cBioPortal in 1 sample across 1 study and 1 cancer type; somatic enrichment level: NONE (Observed in at most one deduplicated cBioPortal case.). This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• 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: 289 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Orphanet, Ambry Genetics

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -5 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	B1High frequency in general population		GnomAD effective popmax AF >1% — B1 stand-alone benign; GnomAD effective popmax AF = 0.0331 — exceeds 1% threshold (B1 applied)
	B3Computational evidence does not support deleterious effect		Computational evidence does not support a deleterious effect; Missense variant — primary computational scorer does not support an oncogenic/deleterious effect; supports B3

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000176.3. You can select a different transcript below to see updated classification 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	Prot: NP_000167.1 UniProt:
	NR3C1 NM_001024094.2		c.1088A>G p.Asn363Ser	missense	Exon 2 of 9	Prot: NP_001019265.1 UniProt:
	NR3C1 NM_001364183.2		c.1088A>G p.Asn363Ser	missense	Exon 3 of 10	Prot: NP_001351112.1 UniProt:

NR3C1 NM_000176.3

MANE Select

HGVSc / HGVSpc.1088A>Gp.Asn363Ser

Exon rankExon 2 of 9

missense

Prot: NP_000167.1UniProt: F1D8N4P04150-1

NR3C1 NM_001024094.2

HGVSc / HGVSpc.1088A>Gp.Asn363Ser

Exon rankExon 2 of 9

missense

Prot: NP_001019265.1UniProt: E5KQF6P04150-3

NR3C1 NM_001364183.2

HGVSc / HGVSpc.1088A>Gp.Asn363Ser

Exon rankExon 3 of 10

missense

Prot: NP_001351112.1UniProt: E5KQF6P04150-3

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	NR3C1 ENST00000394464.7	TSL:1MANE Select	c.1088A>G p.Asn363Ser	missense	Exon 2 of 9	Prot: ENSP00000377977.2 UniProt:
	NR3C1 ENST00000231509.7	TSL:1	c.1088A>G p.Asn363Ser	missense	Exon 2 of 9	Prot: ENSP00000231509.3 UniProt:
	NR3C1 ENST00000504572.5	TSL:1	c.1088A>G p.Asn363Ser	missense	Exon 3 of 10	Prot: ENSP00000422518.1 UniProt:

NR3C1 ENST00000394464.7

TSL:1MANE Select

HGVSc / HGVSpc.1088A>Gp.Asn363Ser

Exon rankExon 2 of 9

missense

Prot: ENSP00000377977.2UniProt: P04150-1

NR3C1 ENST00000231509.7

TSL:1

HGVSc / HGVSpc.1088A>Gp.Asn363Ser

Exon rankExon 2 of 9

missense

Prot: ENSP00000231509.3UniProt: P04150-3

NR3C1 ENST00000504572.5

TSL:1

HGVSc / HGVSpc.1088A>Gp.Asn363Ser

Exon rankExon 3 of 10

missense

Prot: ENSP00000422518.1UniProt: P04150-3

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0192	AC:2915	Hom:41	AN:152158	Cov:32
GnomAD2 exomes	AF: 0.0197	AC:4944	Hom:	AN:251480	Cov:
GnomAD4 exome	AF: 0.0279	AC:40773	Hom:655	AN:1461850	Cov:32
GnomAD4 genome	AF: 0.0191	AC:2915	Hom:41	AN:152276	Cov:32
TOPMed (Bravo)	AF: 0.0180	AC:4764	Hom:70	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0276	AC:12412	Hom:134	AN:449682	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.0145	AC:34	Hom:0	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.000197	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.0200	AC:6	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.0220	AC:286	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.00433	AC:15	Hom:	AN:3478	Cov:
Qatari Genome	AF: 0.00450	AC:9	Hom:	AN:2010	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.00000800	AC:1	Hom:0	AN:122640	Cov:
Turkish Variome	AF: 0.0119	AC:80	Hom:3	AN:6722	Cov:
UK10K	AF: 0.0325	AC:246	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.000112	AC:1	Hom:0	AN:8960	Cov:

Showing 16 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.0414 *	460	11112	0.0397 *	699	17618
BipEx(Bipolar disorder (including schizoaffective))	0.0330	939	28420	0.0358	1034	28844
Epi25(Epilepsy)	0.0263	1104	41958	0.0255	1707	66888
SCHEMA(Schizophrenia)	0.0170	2070	121674	0.0213	4062	190982

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

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

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	17
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
FuncVEP CTI	Benign	0.0013
GPN-Star LLR	N/A	-3.6
GPN-Star score	N/A	3.6
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0079	T
MetaSVM	Benign	-1.1	T
Mutation Taster	N/A	100/0	polymorphism (auto)
MutationAssessor	Benign	1.3	L
PhyloP100	Benign	0.83
popEVE	Benign	-3.0
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.090	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Benign	0.052
Sift	Benign	0.69	T
Sift4G	Benign	1.0	T
Varity_R	N/A	0.031
VESM-3B	Benign	-1.8

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.020
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs56149945;

hg19: chr5-142779317;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar