chr17-42322474-C-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The ENST00000264657.10(STAT3):c.1909G>A(p.Val637Met) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V637A) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
STAT3
ENST00000264657.10 missense
ENST00000264657.10 missense
Scores
12
6
1
Clinical Significance
Conservation
PhyloP100: 7.91
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 17 ACMG points.
PM1
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in ENST00000264657.10
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-42322474-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2138014.Status of the report is criteria_provided_single_submitter, 1 stars.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), STAT3. . Gene score misZ 4.9943 (greater than the threshold 3.09). Trascript score misZ 7.3744 (greater than threshold 3.09). GenCC has associacion of gene with hyper-IgE recurrent infection syndrome 1, autosomal dominant, STAT3-related early-onset multisystem autoimmune disease, permanent neonatal diabetes mellitus.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.908
PP5
Variant 17-42322474-C-T is Pathogenic according to our data. Variant chr17-42322474-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 18308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-42322474-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| STAT3 | NM_139276.3 | c.1909G>A | p.Val637Met | missense_variant | 21/24 | ENST00000264657.10 | NP_644805.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| STAT3 | ENST00000264657.10 | c.1909G>A | p.Val637Met | missense_variant | 21/24 | 1 | NM_139276.3 | ENSP00000264657 | A1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hyper-IgE recurrent infection syndrome 1, autosomal dominant Pathogenic:3Other:1
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 18, 2007 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Department of Immunology, University Hospital Southampton NHSFT | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | The variant is not observed in the gnomAD v2.1.1 dataset. It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID:17881745). Missense changes are a common disease-causing mechanism. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 21792878, 27799162). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.80; 3Cnet: 0.35). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 17881745, 18706697) and observed in multiple (>3) similarly affected unrelated individuals (PMID: 17881745, 18706697, 21792878). Different missense changes at the same codon (p.Val637Ala, p.Val637Leu) have been reported to be associated with STAT3-related disorder (PMID: 17881745, 20159255). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 28, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect on transcriptional activity (Zhou et al., 2021); This variant is associated with the following publications: (PMID: 34466250, 17881745, 23659370, 18706697, 25038750, 27167980, 21288777, 22084479, 21792878, 27091139, 26293184, 28983403, 30410549, 31596517, 32047500, 32912316, 32768442, 32915432, 32944025, 32888943, 33717144, 33726816, 33864888, 22751495, 22591296, 32248557, 31737384, 36292796, 27799162, 29402895, 34824272, 23830147) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 15, 2019 | - - |
Hyper-IgE syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 16, 2017 | Variant summary: The STAT3 c.1909G>A (p.Val637Met) variant involves the alteration of a conserved nucleotide and is located in SH2 domain of the protein. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant has been reported in several patients with Hyper IgE syndrome, including evidences of reported de novo occurrence and cosegregation with disease and is absent in 121926 control chromosomes. Functional studies showed that p.V637M affects the STAT3 function (Tamassia_2010, Giacomelli_2011). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as "pathogenic". - |
Hyper-IgE recurrent infection syndrome 1, autosomal dominant;C4288261:STAT3 gain of function Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 03, 2024 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 637 of the STAT3 protein (p.Val637Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hyper-IgE syndrome (PMID: 17881745, 18706697, 21792878). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 18308). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt STAT3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects STAT3 function (PMID: 26384563, 27799162). For these reasons, this variant has been classified as 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
Uncertain
D
LIST_S2
Pathogenic
.;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M;.;M;M
MutationTaster
Benign
A;A;A;A;A
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;.;D;.;D
REVEL
Pathogenic
Sift
Uncertain
D;.;D;.;D
Sift4G
Pathogenic
D;D;D;D;D
Polyphen
D;.;.;D;D
Vest4
MutPred
Gain of disorder (P = 0.0725);Gain of disorder (P = 0.0725);.;Gain of disorder (P = 0.0725);Gain of disorder (P = 0.0725);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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