Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting
The NM_015122.3(FCHO1):c.97C>G(p.Leu33Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,466 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. L33P) has been classified as Uncertain significance.
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
?
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;
BS1
?
BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00000547 (8/1461282) while in subpopulation AMR AF= 0.000179 (8/44724). AF 95% confidence interval is 0.0000886. There are 0 homozygotes in gnomad4_exome. There are 2 alleles in male gnomad4_exome subpopulation. Median coverage is 30. 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
Sep 21, 2022
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 sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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: "Tolerated"; 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 present in population databases (rs771754784, gnomAD 0.02%). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 33 of the FCHO1 protein (p.Leu33Val). -
Loss of catalytic residue at L33 (P = 0.0554);Loss of catalytic residue at L33 (P = 0.0554);Loss of catalytic residue at L33 (P = 0.0554);Loss of catalytic residue at L33 (P = 0.0554);Loss of catalytic residue at L33 (P = 0.0554);Loss of catalytic residue at L33 (P = 0.0554);Loss of catalytic residue at L33 (P = 0.0554);Loss of catalytic residue at L33 (P = 0.0554);Loss of catalytic residue at L33 (P = 0.0554);Loss of catalytic residue at L33 (P = 0.0554);Loss of catalytic residue at L33 (P = 0.0554);Loss of catalytic residue at L33 (P = 0.0554);Loss of catalytic residue at L33 (P = 0.0554);Loss of catalytic residue at L33 (P = 0.0554);Loss of catalytic residue at L33 (P = 0.0554);Loss of catalytic residue at L33 (P = 0.0554);Loss of catalytic residue at L33 (P = 0.0554);Loss of catalytic residue at L33 (P = 0.0554);.;