rs202210810

Positions:

chr9-101427534-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_000035.4(ALDOB):c.488C>T(p.Ala163Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,614,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

ALDOB
NM_000035.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:4

Conservation

PhyloP100: 8.01

Variant links:

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]

ALDOB links:

ALDOB (HGNC:):

ALDOB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1

In a helix (size 18) in uniprot entity ALDOB_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000035.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.83

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDOB	NM_000035.4 linkuse as main transcript	c.488C>T	p.Ala163Val	missense_variant	5/9	ENST00000647789.2	NP_000026.2	P05062A0A024R145

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDOB	ENST00000647789.2 linkuse as main transcript	c.488C>T	p.Ala163Val	missense_variant	5/9		NM_000035.4	ENSP00000497767.1		P05062

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000143

AC:

AN:

251134

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135734

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000508

Gnomad NFE exome

AF:

0.000185

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000127

AC:

185

AN:

1461882

Hom.:

Cov.:

AF XY:

0.000122

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000693

Gnomad4 NFE exome

AF:

0.000121

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000105

Hom.:

Bravo

AF:

0.0000793

ExAC

AF:

0.000214

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 06, 2016	The A163V variant in the ALDOB gene has been reported previously as a heterozygous variant identified in a newborn as part of a population based study of ALDOB variant frequency (Santer et al., 2005); however A163V has not been identified in an individual with hereditary fructose intolerance. The A163V variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A163V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Alanine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The A163V variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 21, 2018	- -

Hereditary fructosuria

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 12, 2021	This sequence change replaces alanine with valine at codon 163 of the ALDOB protein (p.Ala163Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs202210810, ExAC 0.06%). This missense change has been observed in individual(s) with abdominal pain, gastroesophageal reflux, vomiting, gastroparesis, failure to thrive, anorexia, fructose intolerance (Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 389159). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Elsea Laboratory, Baylor College of Medicine	Apr 01, 2020	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 03, 2022

Variant summary: ALDOB c.488C>T (p.Ala163Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 251134 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ALDOB causing Hereditary Fructose Intolerance (0.00014 vs 0.0045), allowing no conclusion about variant significance. c.488C>T has been reported in the heterozygous state in a cohort of 2,000 randomly selected neonates, which represents carrier status (Santer_2005). This report does not provide unequivocal conclusions about association of the variant with Hereditary Fructose Intolerance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Three submitters classified the variant as VUS while one classified as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.90

D;D;D;T;D;.

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

.;.;.;D;D;D

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.83

D;D;D;D;D;D

MetaSVM

Uncertain

0.74

MutationAssessor

Pathogenic

3.3

M;M;M;.;M;.

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-3.7

D;.;.;.;.;.

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

D;.;.;.;.;.

Sift4G

Uncertain

0.029

D;.;.;D;.;.

Polyphen

1.0

D;D;D;.;D;.

Vest4

0.78

MVP

0.94

MPC

0.12

ClinPred

0.83

GERP RS

5.3

Varity_R

0.85

gMVP

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over