rs886039434
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_Very_Strong
The NM_139276.3(STAT3):c.1979T>C(p.Met660Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
STAT3
NM_139276.3 missense
NM_139276.3 missense
Scores
10
5
3
Clinical Significance
Conservation
PhyloP100: 9.32
Genes affected
STAT3 (HGNC:11364): (signal transducer and activator of transcription 3) The protein encoded by this gene is a member of the STAT protein family. In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. This protein is activated through phosphorylation in response to various cytokines and growth factors including IFNs, EGF, IL5, IL6, HGF, LIF and BMP2. This protein mediates the expression of a variety of genes in response to cell stimuli, and thus plays a key role in many cellular processes such as cell growth and apoptosis. The small GTPase Rac1 has been shown to bind and regulate the activity of this protein. PIAS3 protein is a specific inhibitor of this protein. This gene also plays a role in regulating host response to viral and bacterial infections. Mutations in this gene are associated with infantile-onset multisystem autoimmune disease and hyper-immunoglobulin E syndrome. [provided by RefSeq, Aug 2020]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 15 ACMG points.
PM1
?
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_139276.3
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, STAT3
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.869
PP5
?
Variant 17-42322404-A-G is Pathogenic according to our data. Variant chr17-42322404-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
STAT3 | NM_139276.3 | c.1979T>C | p.Met660Thr | missense_variant | 21/24 | ENST00000264657.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
STAT3 | ENST00000264657.10 | c.1979T>C | p.Met660Thr | missense_variant | 21/24 | 1 | NM_139276.3 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
STAT3 gain of function;CN031130:Hyper-IgE recurrent infection syndrome 1, autosomal dominant Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 10, 2018 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Met660 amino acid residue in STAT3. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 21792878), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change disrupts protein function (PMID: 28315006, 29868029). This variant has been observed in individuals affected with hyper IgE syndrome, including an individual in which the variant occurred de novo (PMID: PMID: 20816194, 28315006). ClinVar contains an entry for this variant (Variation ID: 265261). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with threonine at codon 660 of the STAT3 protein (p.Met660Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 22, 2016 | The M660T variant has been published in association with hyper IgE syndrome (Schimke et al., 2010). The M660T variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The M660T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position located within the SH2 domain that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic. - |
Hyper-IgE syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 15, 2016 | Variant summary: The STAT3 c.1979T>C (p.Met660Thr) variant involves the alteration of a conserved nucleotide located in the Src homology domain 2 of STAT3 and results in a replacement of a medium size and hydrophobic Methionine (M) with a medium size and polar Threonine (T). 4/4 in silico tools predict a damaging outcome for this substitution (SNPs&GO not captured due to low reliability index). This variant is absent in 121612 control chromosomes while it was reported in Hyper IgE Syndrome patients indicating pathogenicity. Moreover, in one patient, the variant emerged de novo strongly suggesting a deleterious outcome. Studies assessing the impact the variant may have on the function of the STAT3 protein were not published at the time of classification. Taken together, this variant is classified as probably pathogenic. - |
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
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M;.;M;M
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;.;D;.;D
REVEL
Pathogenic
Sift
Benign
D;.;D;.;D
Sift4G
Benign
T;T;T;T;T
Polyphen
P;.;.;P;P
Vest4
MutPred
Loss of stability (P = 0.0272);Loss of stability (P = 0.0272);.;Loss of stability (P = 0.0272);Loss of stability (P = 0.0272);
MVP
MPC
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