rs181639417

Positions:

• chr9-101435708-C-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_Moderate PM2 PP3_Strong PP5_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
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product 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: 8 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74422

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000604

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary fructosuria Pathogenic:6

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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	34
DANN	Uncertain	0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.60		Position offset: -3
DS_DL_spliceai		0.98		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs181639417; hg19: chr9-104197990;