Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM2PM5BP4_ModerateBS1_Supporting
The NM_015122.3(FCHO1):c.101C>T(p.Ala34Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000304 in 1,613,102 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM5
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
Computational evidence support a benign effect (MetaRNN=0.15079111).
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000092 (14/152222) while in subpopulation AMR AF= 0.000786 (12/15272). AF 95% confidence interval is 0.000453. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Uncertain significance, criteria provided, single submitter
clinical testing
Invitae
Dec 27, 2023
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 34 of the FCHO1 protein (p.Ala34Val). This variant is present in population databases (rs201598105, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with FCHO1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1364560). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -