17-28575154-A-G

Variant names:

• chr17-28575154-A-G
• rs763025884
• NM_005165.3:c.293T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005165.3(ALDOC):​c.293T>C​(p.Ile98Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ALDOC NM_005165.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

Genes affected

ALDOC (HGNC:418): (aldolase, fructose-bisphosphate C) This gene encodes a member of the class I fructose-biphosphate aldolase gene family. Expressed specifically in the hippocampus and Purkinje cells of the brain, the encoded protein is a glycolytic enzyme that catalyzes the reversible aldol cleavage of fructose-1,6-biphosphate and fructose 1-phosphate to dihydroxyacetone phosphate and either glyceraldehyde-3-phosphate or glyceraldehyde, respectively. [provided by RefSeq, Jul 2008]

RSKR (HGNC:26314): (ribosomal protein S6 kinase related) Predicted to enable protein kinase activity. Predicted to be involved in protein phosphorylation. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDOC	NM_005165.3	c.293T>C	p.Ile98Thr	missense_variant	Exon 3 of 9	ENST00000226253.9	NP_005156.1
ALDOC	XM_005257949.3	c.293T>C	p.Ile98Thr	missense_variant	Exon 4 of 10		XP_005258006.1
ALDOC	XM_011524556.3	c.293T>C	p.Ile98Thr	missense_variant	Exon 4 of 10		XP_011522858.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDOC	ENST00000226253.9	c.293T>C	p.Ile98Thr	missense_variant	Exon 3 of 9	1	NM_005165.3	ENSP00000226253.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 250968 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135628

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461858 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727228

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.293T>C (p.I98T) alteration is located in exon 3 (coding exon 2) of the ALDOC gene. This alteration results from a T to C substitution at nucleotide position 293, causing the isoleucine (I) at amino acid position 98 to be replaced by a threonine (T). 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	0.81
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	25
DANN	Benign	0.95
DEOGEN2	Pathogenic	0.90	D;D;D;D;D;.;.;D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	3.8	.;H;H;.;.;.;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.9	D;D;D;.;.;.;D;.
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D;D;D;.;.;.;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D;.;D;.;.
Polyphen		0.84	P;P;P;.;.;.;.;.
Vest4		0.84
MutPred		0.84		Gain of phosphorylation at I98 (P = 0.059);Gain of phosphorylation at I98 (P = 0.059);Gain of phosphorylation at I98 (P = 0.059);Gain of phosphorylation at I98 (P = 0.059);Gain of phosphorylation at I98 (P = 0.059);.;Gain of phosphorylation at I98 (P = 0.059);Gain of phosphorylation at I98 (P = 0.059);
MVP		0.91
MPC		1.5
ClinPred		0.85	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.92

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: rs763025884; hg19: chr17-26902172;