10-101770490-AGCCCTTGCGGGGCCG-A
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM4PP5
The NM_033163.5(FGF8):c.559_573delCGGCCCCGCAAGGGC(p.Arg187_Gly191del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.000000684 in 1,461,376 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_033163.5 conservative_inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461376Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 727030
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Identified in siblings with holoprosencephaly in published literature (Hong et al., 2016); Published Zebrafish model showed a complete loss of biological activity (Hong et al., 2016); In-frame deletion of 5 amino acids in a non-repeat region; Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26931467) -
This variant, c.559_573del, results in the deletion of 5 amino acid(s) of the FGF8 protein (p.Arg187_Gly191del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of FGF8-related conditions (PMID: 26931467). This variant is also known as c.515-529delCCCGCAAGGGCCGGC. ClinVar contains an entry for this variant (Variation ID: 545457). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects FGF8 function (PMID: 26931467). 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. -
Holoprosencephaly sequence Pathogenic:1
Family history of similarly affected female sibs with evidence of digenic inheritance of a paternal LOF allele in FGF8 and a maternal LOF allele in FGFR1. Established gene to gene interactions in animal models. This FGF8 variation is supported by experimental data and ACMG criteria: PS3;PM1/PM2/PM4;PP1. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at