rs181639417
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000035.4(ALDOB):c.-11+1G>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000525 in 152,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000035.4 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ALDOB | NM_000035.4 | c.-11+1G>C | splice_donor_variant, intron_variant | Intron 1 of 8 | ENST00000647789.2 | NP_000026.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152128Hom.: 0 Cov.: 32
GnomAD4 exome Cov.: 0
GnomAD4 genome AF: 0.0000525 AC: 8AN: 152244Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74422
ClinVar
Submissions by phenotype
Hereditary fructosuria Pathogenic:6
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NM_000035.3(ALDOB):c.-11+1G>C is a canonical splice variant classified as likely pathogenic in the context of hereditary fructose intolerance. c.-11+1G>C has been observed in cases with relevant disease (PMID: 20882353). Functional assessments of this variant are available in the literature (PMID: 20882353). c.-11+1G>C has been observed in population frequency databases (gnomAD: AMR 0.12%). In summary, NM_000035.3(ALDOB):c.-11+1G>C is a canonical splice variant that has functional support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Variant summary: Variant affects a conserved nucleotide located at the donor splice site of the first exon. Mutation taster predicts the variant to be disease causing and 5/5 in silico tools predict the variant to result in the elimination of the splice donor site. The variant was found in the cohort of 1000G at a very low allele frequency (1/5008). It was also reported in HFI patients with potentially pathogenic ALDOB mutation in trans indicating pathogenicity. Furthermore, the variant was shown to result in aberrant splicing leading to complete retention of the first intron and consequently to the loss of ALDOB expression (Coffee_JIMD_2010). A reputable database classifies variant as pathogenic (without evidence to impenitently evaluate). Considering all evidence, the variant was classified as Pathogenic. -
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This sequence change falls in intron 1 of the ALDOB gene. It does not directly change the encoded amino acid sequence of the ALDOB protein. This variant is present in population databases (rs181639417, gnomAD 0.1%). This variant has been observed in individual(s) with fructose intolerance (PMID: 20882353; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS1+1G>C. ClinVar contains an entry for this variant (Variation ID: 495347). Studies have shown that this variant alters ALDOB gene expression (PMID: 20882353). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at