rs769031989
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP2PP5
The ENST00000264657.10(STAT3):c.1919A>T(p.Tyr640Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Synonymous variant affecting the same amino acid position (i.e. Y640Y) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
STAT3
ENST00000264657.10 missense
ENST00000264657.10 missense
Scores
2
12
5
Clinical Significance
Conservation
PhyloP100: 8.02
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 Likely_pathogenic. Variant got 6 ACMG points.
PM1
In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in ENST00000264657.10
PM2
Very rare variant in population databases, with high coverage;
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.
PP5
Variant 17-42322464-T-A is Pathogenic according to our data. Variant chr17-42322464-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 372521.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, other=1, Uncertain_significance=2}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| STAT3 | NM_139276.3 | c.1919A>T | p.Tyr640Phe | 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.1919A>T | p.Tyr640Phe | missense_variant | 21/24 | 1 | NM_139276.3 | ENSP00000264657 | A1 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152218Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461818Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727206
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GnomAD4 genome 0.00000657 AC: 1AN: 152218Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74366
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:2Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Malignant lymphoma, large B-cell, diffuse Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Department Of Pathology & Laboratory Medicine, University Of Pennsylvania | Dec 04, 2023 | Pre-therapy specimen. - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 31, 2016 | The Y640F variant has been observed as a somatic variant in multiple individuals with lymphocytic leukemia (Koskela et al., 2012; Kristensen et al., 2014; Tanahashi et al., 2016). However, it has not been published in association with Hyper-IgE syndrome to our knowledge. The 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. Y640F 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 within the critical SH2 domain that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, functional studies have shown that Y640F is a gain-of-function variant that leads to increased cell selection (Koskela et al., 2012; Küçük et al., 2015). Therefore, we consider the variant to be pathogenic. - |
EBV-positive nodal T- and NK-cell lymphoma Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Department of Clinical Pathology, School of Medicine, Fujita Health University | - | - - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 22, 2024 | Variant summary: STAT3 c.1919A>T (p.Tyr640Phe) results in a conservative amino acid change located in the Src homology 2 (SH2) domain (IPR000980) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.9e-06 in 1614036 control chromosomes (gnomAD). c.1919A>T has been reported in the literature in individuals affected with features of Autoimmune Disease, Multisystem, Infantile-Onset, 1 (Hadjadj_2019, Leiding_2023). These data indicate that the variant may be associated with disease. The p.Tyr640Phe variant has also been frequently reported as a GoF somatic mutation in individuals affected with lymphoid neoplasms and other cancer phenotypes (see e.g. Pilati_2011, Koskela_2012, Jerez_2012, Jerez_2013, Crescenzo_2015, and in the COSMIC database). Additionally, the variant has been reported in one patient as a somatic variant in a T-lymphocyte subpopulation, which resulted in an aberrant cytokine production by the aberrant T-cell clone with consequential secondary hypereosinophilia; of note, this patient also had a high level of IgE, suggesting that somatic c.1919A>T also may be associated with hyper IgE phenotype (Walker_2016). Multiple functional studies demonstrated that the variant results in a highly increased transcriptional activity of STAT3 even in the absence of IL-6 stimulation, demonstrating that it is a gain-of-function mutation (e.g. Pilati_2011, Koskela_2012, Crescenzo_2015, Bahal_2019, Jagle_2019, Parri_2020, Kasembeli_2023, Brandstoetter_2023). The following publications have been ascertained in the context of this evaluation (PMID: 22591296, 25873174, 21690253, 26702067, 23926297, 22859607, 31737384, 30940614, 32231398, 31770611, 36240433, 36228738, 36630607). ClinVar contains an entry for this variant (Variation ID: 372521). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Hyper-IgE recurrent infection syndrome 1, autosomal dominant;C4288261:STAT3 gain of function Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 25, 2023 | This sequence change replaces tyrosine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 640 of the STAT3 protein (p.Tyr640Phe). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Evans syndrome as a germline variant. It is also a common somatic variant observed in individuals with T cell large granular lymphocytic leukemia (PMID: 22591296, 30940614). ClinVar contains an entry for this variant (Variation ID: 372521). 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 not expected to disrupt STAT3 protein function. Experimental studies have shown that this missense change affects STAT3 function (PMID: 22591296, 25873174, 29162862, 29180260, 31771617). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Neoplasm Other:1
| -, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;D;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Benign
L;L;.;L;L
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;.;D;.;D
REVEL
Uncertain
Sift
Benign
T;.;T;.;T
Sift4G
Benign
T;T;T;T;T
Polyphen
D;.;.;D;D
Vest4
MutPred
Loss of ubiquitination at K642 (P = 0.0603);Loss of ubiquitination at K642 (P = 0.0603);.;Loss of ubiquitination at K642 (P = 0.0603);Loss of ubiquitination at K642 (P = 0.0603);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at