9-101427580-A-G

Position:

chr9-101427580-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_000035.4(ALDOB):c.442T>C(p.Trp148Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,614,068 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

ALDOB
NM_000035.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:2U:2

Conservation

PhyloP100: 9.32

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDOB	NM_000035.4 linkuse as main transcript	c.442T>C	p.Trp148Arg	missense_variant	5/9	ENST00000647789.2	NP_000026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDOB	ENST00000647789.2 linkuse as main transcript	c.442T>C	p.Trp148Arg	missense_variant	5/9		NM_000035.4	ENSP00000497767	P1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152182

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

251184

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135770

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000529

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000150

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000189

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74340

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:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary fructosuria

Pathogenic:2Uncertain:1

Pathogenic, no assertion criteria provided	literature only	ATS em Genética Clínica, Universidade Federal do Rio Grande do Sul	Mar 18, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 1995	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 08, 2022	This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 148 of the ALDOB protein (p.Trp148Arg). This variant is present in population databases (rs118204430, gnomAD 0.007%). This missense change has been observed in individual(s) with ALDOB-related conditions (PMID: 7717389). ClinVar contains an entry for this variant (Variation ID: 475). 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. Experimental studies have shown that this missense change affects ALDOB function (PMID: 12417303). 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 26, 2022

Variant summary: ALDOB c.442T>C (p.Trp148Arg) 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 2.8e-05 in 251184 control chromosomes. c.442T>C has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Hereditary Fructose Intolerance (example, Ali_1995 cited in Pinheiro_2021). At least one publication reports experimental evidence evaluating an impact on protein function (example, Rellos_2000). The most pronounced variant effect results in 16-20% of normal aldolase enzyme activity in vitro. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, until additional clinical reports supported by published/peer consensus are obtained, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

D;D;D;D;D;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.99

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

.;.;.;D;D;D

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.3

H;H;H;.;H;.

MutationTaster

Benign

1.0

A;A

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-13

D;.;.;.;.;.

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

D;.;.;.;.;.

Sift4G

Pathogenic

0.0

D;.;.;D;.;.

Polyphen

1.0

D;D;D;.;D;.

Vest4

0.93

MutPred

0.95

Gain of disorder (P = 0.0169);Gain of disorder (P = 0.0169);Gain of disorder (P = 0.0169);Gain of disorder (P = 0.0169);Gain of disorder (P = 0.0169);Gain of disorder (P = 0.0169);

MVP

0.96

MPC

0.14

ClinPred

1.0

GERP RS

6.2

Varity_R

0.99

gMVP

0.95

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