rs121909534

Variant names:

• chr16-30069384-G-A
• rs121909534
• NM_001243177.4:c.781G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001243177.4(ALDOA):​c.781G>A​(p.Glu261Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,890 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ALDOA NM_001243177.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.41
• Publications: 8 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_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959
• PP5: Variant 16-30069384-G-A is Pathogenic according to our data. Variant chr16-30069384-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 18178.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDOA	NM_001243177.4	c.781G>A	p.Glu261Lys	missense_variant	Exon 7 of 10	ENST00000642816.3	NP_001230106.1
LOC112694756	NM_001365304.2	c.*1128G>A		3_prime_UTR_variant	Exon 11 of 14	ENST00000338110.11	NP_001352233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDOA	ENST00000642816.3	c.781G>A	p.Glu261Lys	missense_variant	Exon 7 of 10		NM_001243177.4	ENSP00000496166.1
ENSG00000285043	ENST00000338110.11	c.*1128G>A		3_prime_UTR_variant	Exon 11 of 14	1	NM_001365304.2	ENSP00000336927.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

HNSHA due to aldolase A deficiency Pathogenic:1

Apr 25, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	.;D;D;D;D;.;D;.;D;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;.;.;.;.;.;D;D;D;.;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Pathogenic	3.9	.;H;H;H;H;.;H;.;.;.;.
PhyloP100		9.4
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.4	.;D;D;D;D;D;.;.;D;D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.018	.;D;D;D;D;D;.;.;D;D;D
Sift4G	Benign	0.092	T;T;T;T;T;T;.;.;T;T;D
Polyphen		0.85	.;P;P;P;P;.;P;.;.;.;.
Vest4		0.73
MutPred		0.85		.;Gain of MoRF binding (P = 0.0163);Gain of MoRF binding (P = 0.0163);Gain of MoRF binding (P = 0.0163);Gain of MoRF binding (P = 0.0163);.;Gain of MoRF binding (P = 0.0163);.;Gain of MoRF binding (P = 0.0163);.;.;
MVP		0.95
ClinPred		1.0	D
GERP RS		5.9
PromoterAI		0.029	Neutral
Varity_R		0.83
gMVP		0.85
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.010		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: rs121909534; hg19: chr16-30080705;