Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3PP5_Moderate
The NM_001083962.2(TCF4):c.655+2_655+3insGT variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).
TCF4 (HGNC:11634): (transcription factor 4) This gene encodes transcription factor 4, a basic helix-loop-helix transcription factor. The encoded protein recognizes an Ephrussi-box ('E-box') binding site ('CANNTG') - a motif first identified in immunoglobulin enhancers. This gene is broadly expressed, and may play an important role in nervous system development. Defects in this gene are a cause of Pitt-Hopkins syndrome. In addition, an intronic CTG repeat normally numbering 10-37 repeat units can expand to >50 repeat units and cause Fuchs endothelial corneal dystrophy. Multiple alternatively spliced transcript variants that encode different proteins have been described. [provided by RefSeq, Jul 2016]
Verdict is Uncertain_significance. Variant got 5 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;
PP3
?
PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
PP5
?
PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 18-55279548-T-TAC is Pathogenic according to our data. Variant chr18-55279548-T-TAC is described in ClinVar as [Pathogenic]. Clinvar id is 212381.Status of the report is criteria_provided_single_submitter, 1 stars.