16-30069634-G-A

Variant names:

• chr16-30069634-G-A
• rs142759891
• NM_001243177.4:c.922G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001243177.4(ALDOA):​c.922G>A​(p.Val308Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00025 in 1,613,804 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V308L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (1 hom.)
• Consequence: ALDOA NM_001243177.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 8.06
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• glycogen storage disease due to aldolase A deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

LOC112694756 (HGNC:0):

ENSG00000285043 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18625683).
• BP6: Variant 16-30069634-G-A is Benign according to our data. Variant chr16-30069634-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 450306.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001243177.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDOA	NM_001243177.4	MANE Select	c.922G>A	p.Val308Ile	missense	Exon 8 of 10	NP_001230106.1
	LOC112694756	NM_001365304.2	MANE Select	c.*1269G>A		3_prime_UTR	Exon 12 of 14	NP_001352233.1
	ALDOA	NM_001127617.2		c.760G>A	p.Val254Ile	missense	Exon 7 of 9	NP_001121089.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDOA	ENST00000642816.3	MANE Select	c.922G>A	p.Val308Ile	missense	Exon 8 of 10	ENSP00000496166.1
	ALDOA	ENST00000412304.6	TSL:1	c.760G>A	p.Val254Ile	missense	Exon 7 of 9	ENSP00000400452.2
	ALDOA	ENST00000563060.6	TSL:1	c.760G>A	p.Val254Ile	missense	Exon 7 of 9	ENSP00000455800.2

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152162 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000192 AC: 48 AN: 250576 AF XY: 0.000244

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000141

Gnomad NFE exome AF: 0.000168

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000260 AC: 380 AN: 1461524 Hom.: 1 Cov.: 32 AF XY: 0.000286 AC XY: 208 AN XY: 727098

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.000719 AC: 62 AN: 86256

European-Finnish (FIN) AF: 0.000188 AC: 10 AN: 53072

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000243 AC: 270 AN: 1112004

Other (OTH) AF: 0.000480 AC: 29 AN: 60392

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152280 Hom.: 1 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74458

African (AFR) AF: 0.0000962 AC: 4 AN: 41562

American (AMR) AF: 0.000131 AC: 2 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4830

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000236 Hom.: 1

Bravo AF: 0.000181

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000214 AC: 26

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

HNSHA due to aldolase A deficiency Uncertain:1 Benign:1

Jun 14, 2024

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Uncertain:1

Jul 18, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The V254I variant in the ALDOA gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The V254I variant is observed in 11/16490 (0.07%) alleles from individuals of South Asian background and in 13/66398 (0.02%) alleles from individuals of non-Finnish European background, in the ExAC dataset (Lek et al., 2016). The V254I 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 that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret V254I as a variant of uncertain significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.19	T
MetaSVM	Uncertain	0.54	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		8.1
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.56	N
REVEL	Uncertain	0.49
Sift	Benign	0.068	T
Sift4G	Benign	0.23	T
Polyphen		0.55	P
Vest4		0.36
MVP		0.92
ClinPred		0.066	T
GERP RS		5.9
PromoterAI		0.012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.30
gMVP		0.53
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs142759891; hg19: chr16-30080955;