chr5-143400691-A-C

Variant names:

• chr5-143400691-A-C
• rs79138720
• NM_000176.3:c.149T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000176.3(NR3C1):​c.149T>G​(p.Val50Gly) 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. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NR3C1 NM_000176.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.739
• Publications: 6 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.068365455).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR3C1	NM_000176.3	c.149T>G	p.Val50Gly	missense_variant	Exon 2 of 9	ENST00000394464.7	NP_000167.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR3C1	ENST00000394464.7	c.149T>G	p.Val50Gly	missense_variant	Exon 2 of 9	1	NM_000176.3	ENSP00000377977.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	12
DANN	Benign	0.80
DEOGEN2	Benign	0.16	T;T;.;.;.;.;.;T;T;T;T;T;T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.39	.;T;T;T;.;.;T;.;.;.;.;T;T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.068	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.12	N;N;N;N;N;N;N;N;.;.;.;.;.
PhyloP100		0.74
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.22	N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.026
Sift	Benign	0.23	T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.39	T;T;T;T;T;T;T;T;.;.;.;.;T
Polyphen		0.0	B;B;.;.;.;.;.;B;.;.;.;.;.
Vest4		0.099
MutPred		0.36		Loss of stability (P = 0.0259);Loss of stability (P = 0.0259);Loss of stability (P = 0.0259);Loss of stability (P = 0.0259);Loss of stability (P = 0.0259);Loss of stability (P = 0.0259);Loss of stability (P = 0.0259);Loss of stability (P = 0.0259);Loss of stability (P = 0.0259);Loss of stability (P = 0.0259);Loss of stability (P = 0.0259);Loss of stability (P = 0.0259);Loss of stability (P = 0.0259);
MVP		0.23
MPC		0.068
ClinPred		0.10	T
GERP RS		3.3
PromoterAI		0.013	Neutral
Varity_R		0.057
gMVP		0.27
Mutation Taster		=95/5	polymorphism

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: rs79138720; hg19: chr5-142780256;