Genetic Variant ALDOA:p.Ala74Val (chr16-30067313-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001243177.4(ALDOA):c.221C>T(p.Ala74Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,992 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: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ALDOA
NM_001243177.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.86

Variant links:

Genes affected

ALDOA (HGNC:414): (aldolase, fructose-bisphosphate A) This gene encodes a member of the class I fructose-bisphosphate aldolase protein family. The encoded protein is a glycolytic enzyme that catalyzes the reversible conversion of fructose-1,6-bisphosphate to glyceraldehyde 3-phosphate and dihydroxyacetone phosphate. Three aldolase isozymes (A, B, and C), encoded by three different genes, are differentially expressed during development. Mutations in this gene have been associated with Glycogen Storage Disease XII, an autosomal recessive disorder associated with hemolytic anemia. Disruption of this gene also plays a role in the progression of multiple types of cancers. Related pseudogenes have been identified on chromosomes 3 and 10. [provided by RefSeq, Sep 2017]

ALDOA links:

LOC112694756 (HGNC:):

LOC112694756 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.918

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDOA	NM_001243177.4 link	c.221C>T	p.Ala74Val	missense_variant	Exon 3 of 10	ENST00000642816.3	NP_001230106.1	P04075-2
LOC112694756	NM_001365304.2 link	c.*568C>T		3_prime_UTR_variant	Exon 7 of 14	ENST00000338110.11	NP_001352233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDOA	ENST00000642816.3 link	c.221C>T	p.Ala74Val	missense_variant	Exon 3 of 10		NM_001243177.4	ENSP00000496166.1		P04075-2
ENSG00000285043	ENST00000338110.11 link	c.*568C>T		3_prime_UTR_variant	Exon 7 of 14	1	NM_001365304.2	ENSP00000336927.6		A0A2U3TZJ4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1460992

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726808

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Aug 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.59C>T (p.A20V) alteration is located in exon 7 (coding exon 1) of the ALDOA gene. This alteration results from a C to T substitution at nucleotide position 59, causing the alanine (A) at amino acid position 20 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.29

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.37

.;T;D;D;D;D;D;.;D;.;D;.;T;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;.;.;.;D;.;.;D;D;D;.;D;D

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.92

D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.59

MutationAssessor

Pathogenic

3.1

.;.;M;M;M;.;M;.;M;.;.;.;.;.

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.9

.;N;N;N;N;N;N;N;.;.;N;N;N;N

REVEL

Pathogenic

0.77

Sift

Benign

0.032

.;D;D;D;D;D;D;D;.;.;D;D;D;D

Sift4G

Benign

0.076

T;D;T;T;T;D;T;T;.;.;T;T;D;T

Polyphen

0.77

.;.;P;P;P;.;P;.;P;.;.;.;.;.

Vest4

0.85

MutPred

0.80

Loss of disorder (P = 0.0966);Loss of disorder (P = 0.0966);Loss of disorder (P = 0.0966);Loss of disorder (P = 0.0966);Loss of disorder (P = 0.0966);Loss of disorder (P = 0.0966);Loss of disorder (P = 0.0966);.;Loss of disorder (P = 0.0966);.;Loss of disorder (P = 0.0966);Loss of disorder (P = 0.0966);Loss of disorder (P = 0.0966);.;

MVP

0.93

ClinPred

0.96

GERP RS

5.5

Varity_R

0.74

gMVP

0.94

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over