rs181639417
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_000035.4(ALDOB):c.-11+1G>C variant causes a splice donor 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
Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Consequence
ALDOB
NM_000035.4 splice_donor
NM_000035.4 splice_donor
Scores
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 3.70
Genes affected
ALDOB (HGNC:417): (aldolase, fructose-bisphosphate B) Fructose-1,6-bisphosphate aldolase (EC 4.1.2.13) is a tetrameric glycolytic enzyme that catalyzes the reversible conversion of fructose-1,6-bisphosphate to glyceraldehyde 3-phosphate and dihydroxyacetone phosphate. Vertebrates have 3 aldolase isozymes which are distinguished by their electrophoretic and catalytic properties. Differences indicate that aldolases A, B, and C are distinct proteins, the products of a family of related 'housekeeping' genes exhibiting developmentally regulated expression of the different isozymes. The developing embryo produces aldolase A, which is produced in even greater amounts in adult muscle where it can be as much as 5% of total cellular protein. In adult liver, kidney and intestine, aldolase A expression is repressed and aldolase B is produced. In brain and other nervous tissue, aldolase A and C are expressed about equally. There is a high degree of homology between aldolase A and C. Defects in ALDOB cause hereditary fructose intolerance. [provided by RefSeq, Dec 2008]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.05936073 fraction of the gene.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 9-101435708-C-G is Pathogenic according to our data. Variant chr9-101435708-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 495347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALDOB | NM_000035.4 | c.-11+1G>C | splice_donor_variant | ENST00000647789.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALDOB | ENST00000647789.2 | c.-11+1G>C | splice_donor_variant | NM_000035.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152128Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
8
AN:
152128
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome Cov.: 0
GnomAD4 exome
Cov.:
0
GnomAD4 genome ? AF: 0.0000525 AC: 8AN: 152244Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74422
GnomAD4 genome
?
AF:
AC:
8
AN:
152244
Hom.:
Cov.:
32
AF XY:
AC XY:
4
AN XY:
74422
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Bravo
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary fructosuria Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 12, 2023 | 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. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 01, 2021 | 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. - |
Likely pathogenic, no assertion criteria provided | literature only | ATS em Genética Clínica, Universidade Federal do Rio Grande do Sul | Mar 18, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 29, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 12, 2016 | 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -3
DS_DL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at