chr1-23845830-T-TA
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5
The NM_000147.5(FUCA1):c.1285_1286insT(p.Asp429ValfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
FUCA1
NM_000147.5 frameshift
NM_000147.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -1.42
Genes affected
FUCA1 (HGNC:4006): (alpha-L-fucosidase 1) The protein encoded by this gene is a lysosomal enzyme involved in the degradation of fucose-containing glycoproteins and glycolipids. Mutations in this gene are associated with fucosidosis (FUCA1D), which is an autosomal recessive lysosomal storage disease. A pseudogene of this locus is present on chr 2.[provided by RefSeq, Oct 2009]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0828 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 1-23845830-T-TA is Pathogenic according to our data. Variant chr1-23845830-T-TA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1328977.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FUCA1 | NM_000147.5 | c.1285_1286insT | p.Asp429ValfsTer10 | frameshift_variant | 8/8 | ENST00000374479.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FUCA1 | ENST00000374479.4 | c.1285_1286insT | p.Asp429ValfsTer10 | frameshift_variant | 8/8 | 1 | NM_000147.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251364Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135852
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461874Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727240
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Fucosidosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 06, 2023 | This sequence change creates a premature translational stop signal (p.Asp429Valfs*10) in the FUCA1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 38 amino acid(s) of the FUCA1 protein. This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with FUCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1328977). This variant disrupts a region of the FUCA1 protein in which other variant(s) (p.Lys431Glnfs*27) have been determined to be pathogenic (PMID: 36082656). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 03, 2021 | Variant summary: FUCA1 c.1285_1286insT (p.Asp429ValfsX10) located in the last exon results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have not been classified as pathogenic by our laboratory but at-least one downstream extention variant, c.1399T>A (p.*467K), has been reported in the HGMD database and another downstream variant, c.1295G>A (p.Trp432*) has been classified as a VUS by a submitting laboratory in the ClinVar database. The variant allele was found at a frequency of 4e-06 in 251364 control chromosomes. To our knowledge, no occurrence of c.1285_1286insT in individuals affected with Fucosidosis and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at