rs104893914
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_000176.3(NR3C1):c.2035G>A(p.Gly679Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
NR3C1
NM_000176.3 missense
NM_000176.3 missense
Scores
16
2
1
Clinical Significance
Conservation
PhyloP100: 7.90
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 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;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.929
PP5
Variant 5-143282714-C-T is Pathogenic according to our data. Variant chr5-143282714-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 16157.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NR3C1 | NM_000176.3 | c.2035G>A | p.Gly679Ser | missense_variant | 8/9 | ENST00000394464.7 | NP_000167.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NR3C1 | ENST00000394464.7 | c.2035G>A | p.Gly679Ser | missense_variant | 8/9 | 1 | NM_000176.3 | ENSP00000377977.2 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461546Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727062
GnomAD4 exome
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3
AN:
1461546
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Cov.:
32
AF XY:
AC XY:
3
AN XY:
727062
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 31
GnomAD4 genome
Cov.:
31
Bravo
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EpiControl
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Glucocorticoid resistance Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2005 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;.;.;.;.;.;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
.;D;D;D;.;.;D;.
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M;M;.;.;.;.;M
MutationTaster
Benign
A;A;A;A;A;A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;D;D;D
Polyphen
D;D;.;.;.;.;.;D
Vest4
MutPred
Gain of phosphorylation at G679 (P = 0.0327);Gain of phosphorylation at G679 (P = 0.0327);Gain of phosphorylation at G679 (P = 0.0327);.;.;.;.;Gain of phosphorylation at G679 (P = 0.0327);
MVP
MPC
2.4
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at