5-143282715-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_000176.3(NR3C1):​c.2034C>G​(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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: NR3C1 NM_000176.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0830

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a domain NR LBD (size 234) in uniprot entity GCR_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000176.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.067963034).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR3C1	NM_000176.3	c.2034C>G	p.Asp678Glu	missense_variant	Exon 8 of 9	ENST00000394464.7	NP_000167.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR3C1	ENST00000394464.7	c.2034C>G	p.Asp678Glu	missense_variant	Exon 8 of 9	1	NM_000176.3	ENSP00000377977.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	5.9
DANN	Benign	0.73
DEOGEN2	Uncertain	0.76	D;D;.;.;.;.;.;D
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.79	.;T;T;T;.;.;T;.
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.068	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	-0.18	N;N;N;.;.;.;.;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.7	N;N;N;N;N;N;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.82	T;T;T;T;T;T;T;T
Sift4G	Benign	0.48	T;T;T;T;T;T;T;T
Polyphen		0.0	B;B;.;.;.;.;.;B
Vest4		0.12
MutPred		0.34		Loss of ubiquitination at K677 (P = 0.1223);Loss of ubiquitination at K677 (P = 0.1223);Loss of ubiquitination at K677 (P = 0.1223);.;.;.;.;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs258751; hg19: chr5-142662280;