rs185972191

Positions:

• chr9-101435912-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000648064.1(ALDOB):​c.-10-5015G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00679 in 152,140 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0068 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ALDOB ENST00000648064.1 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:2
• Conservation: PhyloP100: 0.904

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 9-101435912-C-T is Benign according to our data. Variant chr9-101435912-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 500745.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=3}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00679 (1033/152140) while in subpopulation AMR AF= 0.00949 (145/15284). AF 95% confidence interval is 0.00881. There are 5 homozygotes in gnomad4. There are 463 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDOB	ENST00000648064.1	c.-10-5015G>A		intron_variant				ENSP00000497990	P1
ALDOB	ENST00000648423.1	c.-64-150G>A		intron_variant				ENSP00000497985
ALDOB	ENST00000648758.1	c.-10-5015G>A		intron_variant				ENSP00000497731	P1

Frequencies

GnomAD3 genomes AF: 0.00680 AC: 1034 AN: 152022 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00210

Gnomad AMI AF: 0.0615

Gnomad AMR AF: 0.00956

Gnomad ASJ AF: 0.0133

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00436

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00941

Gnomad OTH AF: 0.0110

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 10 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 10

Gnomad4 AFR exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.00679 AC: 1033 AN: 152140 Hom.: 5 Cov.: 32 AF XY: 0.00622 AC XY: 463 AN XY: 74398

Gnomad4 AFR AF: 0.00210

Gnomad4 AMR AF: 0.00949

Gnomad4 ASJ AF: 0.0133

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00436

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00941

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00868 Hom.: 1

Bravo AF: 0.00751

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	ALDOB: BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 22, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 07, 2022	BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 2020	Functional studies found that this variant causes loss of transcription from the promoter (Coffee et al., 2010); Nucleotide substitution has no predicted effect on splicing and is not conserved across species; This variant is associated with the following publications: (PMID: 20882353, 25910213) -

Hereditary fructosuria Pathogenic:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 13, 2023	- -
Pathogenic, no assertion criteria provided	literature only	ATS em Genética Clínica, Universidade Federal do Rio Grande do Sul	Mar 18, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	14
DANN	Benign	0.49

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs185972191; hg19: chr9-104198194;