Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM5
The NM_213622.4(STAMBP):c.41G>A(p.Arg14Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,756 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R14P) has been classified as Likely pathogenic.
STAMBP (HGNC:16950): (STAM binding protein) Cytokine-mediated signal transduction in the JAK-STAT cascade requires the involvement of adaptor molecules. One such signal-transducing adaptor molecule contains an SH3 domain that is required for induction of MYC and cell growth. The protein encoded by this gene binds to the SH3 domain of the signal-transducing adaptor molecule, and plays a critical role in cytokine-mediated signaling for MYC induction and cell cycle progression. Multiple alternatively spliced transcript variants encoding the same protein isoform have been found for this gene. [provided by RefSeq, Jul 2008]
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM1
?
PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
In a region_of_interest Interaction with CHMP3 (size 126) in uniprot entity STABP_HUMAN there are 10 pathogenic changes around while only 1 benign (91%) in NM_213622.4
PM2
?
PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PM5
?
PM5 - Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
Uncertain significance, criteria provided, single submitter
clinical testing
Invitae
Dec 03, 2021
This variant has not been reported in the literature in individuals affected with STAMBP-related conditions. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is present in population databases (rs778405428, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 14 of the STAMBP protein (p.Arg14Gln). -
Loss of disorder (P = 0.2218);Loss of disorder (P = 0.2218);Loss of disorder (P = 0.2218);Loss of disorder (P = 0.2218);Loss of disorder (P = 0.2218);Loss of disorder (P = 0.2218);Loss of disorder (P = 0.2218);Loss of disorder (P = 0.2218);