chr17-42322413-T-C
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_139276.3(STAT3):c.1970A>G(p.Tyr657Cys) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y657Q) has been classified as Likely pathogenic.
Frequency
Consequence
NM_139276.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
STAT3 | NM_139276.3 | c.1970A>G | p.Tyr657Cys | missense_variant | 21/24 | ENST00000264657.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
STAT3 | ENST00000264657.10 | c.1970A>G | p.Tyr657Cys | missense_variant | 21/24 | 1 | NM_139276.3 | A1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hyper-IgE recurrent infection syndrome 1, autosomal dominant Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing;curation | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 18, 2011 | - - |
STAT3 gain of function;CN031130:Hyper-IgE recurrent infection syndrome 1, autosomal dominant Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 10, 2022 | Experimental studies have shown that this missense change affects STAT3 function (PMID: 19577286). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. 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. This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 657 of the STAT3 protein (p.Tyr657Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hyper-IgE syndrome (HIES) (PMID: 19577286, 22751495, 23584561, 30617622). ClinVar contains an entry for this variant (Variation ID: 36790). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at