rs786204598
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PVS1PM2PP3PP5_Very_Strong
The NM_000035.4(ALDOB):c.113-1_115delGGTA(p.Gly38_Thr39delinsAla) variant causes a splice acceptor, disruptive inframe deletion, splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,613,886 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000035.4 splice_acceptor, disruptive_inframe_deletion, splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ALDOB | NM_000035.4 | c.113-1_115delGGTA | p.Gly38_Thr39delinsAla | splice_acceptor_variant, disruptive_inframe_deletion, splice_region_variant, intron_variant | 3/9 | ENST00000647789.2 | NP_000026.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ALDOB | ENST00000647789.2 | c.113-1_115delGGTA | p.Gly38_Thr39delinsAla | splice_acceptor_variant, disruptive_inframe_deletion, splice_region_variant, intron_variant | 3/9 | NM_000035.4 | ENSP00000497767.1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152144Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250930Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135658
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461742Hom.: 0 AF XY: 0.00000963 AC XY: 7AN XY: 727168
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152144Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74320
ClinVar
Submissions by phenotype
Hereditary fructosuria Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 21, 2024 | This variant results in the deletion of part of exon 3 (c.113-1_115del) of the ALDOB gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ALDOB are known to be pathogenic (PMID: 18541450). This variant is present in population databases (rs786204598, gnomAD 0.002%). This variant has been observed in individuals with fructose intolerance (PMID: 2349937, 15880727). ClinVar contains an entry for this variant (Variation ID: 188974). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 08, 2023 | Variant summary: ALDOB c.113-1_115delGGTA is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250930 control chromosomes. c.113-1_115delGGTA has been reported in the literature as a homozygous or compound heterozygous genotype in at-least two individuals affected with Hereditary Fructose Intolerance and subsequently cited by others (example, Cross_1990, Ali_1998, Kaiser_1991). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Sep 23, 2014 | - - |
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 | 3billion | Feb 23, 2023 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). This variant was predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (PMID: 2349937). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 24, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at