rs121909534

chr16-30069384-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 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

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_pathogenic. Variant got 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/exons	MANE	UniProt
ALDOA	NM_001243177.4	c.781G>A	p.Glu261Lys	missense_variant	7/10	ENST00000642816.3
LOC112694756	NM_001365304.2	c.*1128G>A		3_prime_UTR_variant	11/14	ENST00000338110.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDOA	ENST00000642816.3	c.781G>A	p.Glu261Lys	missense_variant	7/10		NM_001243177.4
	ENST00000338110.11	c.*1128G>A		3_prime_UTR_variant	11/14	1	NM_001365304.2	P2

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

HNSHA due to aldolase A deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 25, 1996

- -

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
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
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A
PrimateAI	Pathogenic	0.83	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
Varity_R		0.83
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs121909534; hg19: chr16-30080705;