rs587777650
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS1PM1PM2PM5PP2PP3_ModeratePP5_Moderate
The NM_139276.3(STAT3):c.1974G>T(p.Lys658Asn) variant causes a missense change involving the alteration of a non-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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K658R) 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 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
STAT3 | NM_139276.3 | c.1974G>T | p.Lys658Asn | missense_variant | 21/24 | ENST00000264657.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
STAT3 | ENST00000264657.10 | c.1974G>T | p.Lys658Asn | 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
STAT3-related early-onset multisystem autoimmune disease Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Jun 04, 2020 | This STAT3 variant is absent from a large population dataset and has an entry in ClinVar. It has been reported in two unrelated patients with autosomal dominant infantile-onset multisystem autoimmune disease-1. Independent functional studies have shown that the p.Lys658Asn substitution confers hypersensitivity to interleukins resulting in persistent activation of STAT3 signaling in vitro. This variant is not predicted to affect normal exon 21 splicing, although this has not been confirmed experimentally to our knowledge. We consider c.1974G>T to be likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at