chr17-28573869-G-A

Variant names:

• chr17-28573869-G-A
• rs773395204
• NM_005165.3:c.865C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005165.3(ALDOC):​c.865C>T​(p.Arg289Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,614,122 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: ALDOC NM_005165.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.83

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]

ENSG00000265168 (HGNC:56941):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDOC	NM_005165.3	c.865C>T	p.Arg289Cys	missense_variant	Exon 8 of 9	ENST00000226253.9	NP_005156.1
ALDOC	XM_005257949.3	c.865C>T	p.Arg289Cys	missense_variant	Exon 9 of 10		XP_005258006.1
ALDOC	XM_011524556.3	c.865C>T	p.Arg289Cys	missense_variant	Exon 9 of 10		XP_011522858.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDOC	ENST00000226253.9	c.865C>T	p.Arg289Cys	missense_variant	Exon 8 of 9	1	NM_005165.3	ENSP00000226253.4

Frequencies

GnomAD3 genomes AF: 0.0000525 AC: 8 AN: 152242 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000278 AC: 7 AN: 251390 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135870

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

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: 0.0000352

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152242 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74372

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.865C>T (p.R289C) alteration is located in exon 8 (coding exon 7) of the ALDOC gene. This alteration results from a C to T substitution at nucleotide position 865, causing the arginine (R) at amino acid position 289 to be replaced by a cysteine (C). 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	Benign	0.098
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;D;D
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;.;D
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.43	T;T;T
MetaSVM	Uncertain	0.21	D
MutationAssessor	Benign	1.4	.;L;L
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Uncertain	0.48
Sift	Uncertain	0.024	D;D;D
Sift4G	Uncertain	0.011	D;D;D
Polyphen		0.89	P;B;B
Vest4		0.54
MutPred		0.39		.;Loss of solvent accessibility (P = 0.1459);Loss of solvent accessibility (P = 0.1459);
MVP		0.71
MPC		0.62
ClinPred		0.56	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.50

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: rs773395204; hg19: chr17-26900887;