rs142759891

Positions:

• chr16-30069634-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The ENST00000338110.11(ENSG00000285043):​c.*1269G>A variant causes a 3 prime UTR 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).

• Frequency:
  • Genomes: 𝑓 0.00015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (1 hom.)
• Consequence: ENST00000338110.11 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 8.06

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]

LOC112694756 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -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 id is 450306.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDOA	NM_001243177.4	c.922G>A	p.Val308Ile	missense_variant	8/10	ENST00000642816.3	NP_001230106.1
LOC112694756	NM_001365304.2	c.*1269G>A		3_prime_UTR_variant	12/14	ENST00000338110.11	NP_001352233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDOA	ENST00000642816.3	c.922G>A	p.Val308Ile	missense_variant	8/10		NM_001243177.4	ENSP00000496166
	ENST00000338110.11	c.*1269G>A		3_prime_UTR_variant	12/14	1	NM_001365304.2	ENSP00000336927	P2

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

GnomAD3 exomes AF: 0.000192 AC: 48 AN: 250576 Hom.: 1 AF XY: 0.000244 AC XY: 33 AN XY: 135510

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 SAS exome AF: 0.000686

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

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000719

Gnomad4 FIN exome AF: 0.000188

Gnomad4 NFE exome AF: 0.000243

Gnomad4 OTH exome AF: 0.000480

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

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000230 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

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 13, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2023	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 18, 2017

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 v4.3

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;D;D;D;.;D;.;D;.;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;.;.;.;.;.;D;D;D;.;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.54	D
MutationAssessor	Uncertain	2.6	.;M;M;M;M;.;M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.56	.;N;N;N;N;N;.;.;N;N;.
REVEL	Uncertain	0.49
Sift	Benign	0.068	.;T;T;T;T;T;.;.;T;T;.
Sift4G	Benign	0.23	T;T;T;T;T;T;.;.;T;T;T
Polyphen		0.55	.;P;P;P;P;.;P;.;.;.;.
Vest4		0.36
MVP		0.92
ClinPred		0.066	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.30
gMVP		0.53

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

Other links and lift over

dbSNP: rs142759891; hg19: chr16-30080955;