Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PM5BP4
The NM_015122.3(FCHO1):c.100G>A(p.Ala34Thr) 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 benign outcome for this variant. 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. A34P) has been classified as Pathogenic.
FCHO1 (HGNC:29002): (FCH and mu domain containing endocytic adaptor 1) Enables AP-2 adaptor complex binding activity. Involved in clathrin coat assembly and clathrin-dependent endocytosis. Located in cytosol; nucleoplasm; and plasma membrane. Is active in clathrin-coated pit. Implicated in primary immunodeficiency disease. [provided by Alliance of Genome Resources, Apr 2022]
Verdict is Uncertain_significance. Variant got 3 ACMG points.
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 chr19-17762834-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 805884.Status of the report is no_assertion_criteria_provided, 0 stars.
BP4
?
BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (MetaRNN=0.39104515).
Uncertain significance, criteria provided, single submitter
clinical testing
Invitae
Oct 14, 2021
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 has not been reported in the literature in individuals affected with FCHO1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with threonine at codon 34 of the FCHO1 protein (p.Ala34Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. -
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