Submissions for variant NM_001291303.3(FAT4):c.14945_14946del (p.Tyr4982fs)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002726167	SCV003007247	uncertain significance	not provided	2022-11-28	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the FAT4 gene (p.Tyr4980Cysfs*12). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2 amino acid(s) of the FAT4 protein and extend the protein by 9 additional amino acid residues. This variant has not been reported in the literature in individuals affected with FAT4-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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV004559959	SCV005047077	uncertain significance	Hennekam lymphangiectasia-lymphedema syndrome 2	2024-02-12	criteria provided, single submitter	clinical testing	A FAT4 c.14945_14946del (p.Tyr4982Cysfs*12) variant was identified at a heterozygous allelic fraction of 50%, a frequency which may be consistent with germline origin. This variant, to our knowledge, has not been reported in the medical literature, but has been reported in the ClinVar database as a germline variant of uncertain significance by a single submitter. The FAT4 c.14945_14946del (p.Tyr4982Cysfs*12) variant is absent from the general population (gnomAD v4.0.0), indicating it is not a common variant. This variant causes a frameshift by deleting 2 nucleotides, however, because this occurs in the last exon, this is not predicted to lead to nonsense mediated decay, but does lead to an extended protein. Due to limited information, and based on the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time.