Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS1_ModeratePM1PM2PM5PP2PP3_Moderate
The NM_139276.3(STAT3):c.1909G>C(p.Val637Leu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V637A) has been classified as Likely pathogenic.
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]
Verdict is Pathogenic. Variant got 11 ACMG points.
PS1
Transcript NM_139276.3 (STAT3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM1
In a domain SH2 (size 90) in uniprot entity STAT3_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_139276.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-42322473-A-G is described in Lovd as [Likely_pathogenic].
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). The gene has 82 curated pathogenic missense variants (we use a threshold of 10). The gene has 34 curated benign missense variants. GenCC has associacion of the 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, 0.888
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