NM_000176.3:c.2034C>A

Variant names:

• chr5-143282715-G-T
• rs258751
• NM_000176.3:c.2034C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000176.3(NR3C1):​c.2034C>A​(p.Asp678Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D678Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: NR3C1 NM_000176.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0830
• Publications: 22 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: Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ENSG00000300303 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06750068).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C1	NM_000176.3	MANE Select	c.2034C>A	p.Asp678Glu	missense	Exon 8 of 9	NP_000167.1
	NR3C1	NM_001024094.2		c.2037C>A	p.Asp679Glu	missense	Exon 8 of 9	NP_001019265.1
	NR3C1	NM_001364183.2		c.2037C>A	p.Asp679Glu	missense	Exon 9 of 10	NP_001351112.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C1	ENST00000394464.7	TSL:1 MANE Select	c.2034C>A	p.Asp678Glu	missense	Exon 8 of 9	ENSP00000377977.2
	NR3C1	ENST00000231509.7	TSL:1	c.2037C>A	p.Asp679Glu	missense	Exon 8 of 9	ENSP00000231509.3
	NR3C1	ENST00000504572.5	TSL:1	c.2037C>A	p.Asp679Glu	missense	Exon 9 of 10	ENSP00000422518.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	5.0
DANN	Benign	0.73
DEOGEN2	Uncertain	0.76	D
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.068	T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	-0.18	N
PhyloP100		-0.083
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.35
Sift	Benign	0.82	T
Sift4G	Benign	0.48	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.34		Loss of ubiquitination at K677 (P = 0.1223)
MVP		0.64
MPC		1.1
ClinPred		0.038	T
GERP RS		-5.1
Varity_R		0.24
gMVP		0.056
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs258751; hg19: chr5-142662280;