17-3476185-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1PM2PP2BP4_Moderate

The NM_000049.4(ASPA):​c.26A>T​(p.Glu9Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

ASPA
NM_000049.4 missense

Scores

3
16

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 1.23

Publications

0 publications found
Variant links:
Genes affected
ASPA (HGNC:756): (aspartoacylase) This gene encodes an enzyme that catalyzes the conversion of N-acetyl_L-aspartic acid (NAA) to aspartate and acetate. NAA is abundant in the brain where hydrolysis by aspartoacylase is thought to help maintain white matter. This protein is an NAA scavenger in other tissues. Mutations in this gene cause Canavan disease. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2008]
SPATA22 (HGNC:30705): (spermatogenesis associated 22) Predicted to be involved in regulation of meiotic cell cycle. Predicted to act upstream of or within several processes, including fertilization; gamete generation; and meiosis I cell cycle process. Predicted to be located in chromosome. [provided by Alliance of Genome Resources, Apr 2022]
SPATA22 Gene-Disease associations (from GenCC):
  • infertility disorder
    Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000049.4
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 48 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: 0.47868 (below the threshold of 3.09). Trascript score misZ: 1.2423 (below the threshold of 3.09). GenCC associations: The gene is linked to Canavan disease, mild Canavan disease, severe Canavan disease.
BP4
Computational evidence support a benign effect (MetaRNN=0.12987837).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ASPANM_000049.4 linkc.26A>T p.Glu9Val missense_variant Exon 1 of 6 ENST00000263080.3 NP_000040.1 P45381Q6FH48

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ASPAENST00000263080.3 linkc.26A>T p.Glu9Val missense_variant Exon 1 of 6 1 NM_000049.4 ENSP00000263080.2 P45381

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Spongy degeneration of central nervous system Uncertain:1
Mar 06, 2025
Natera, Inc.
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Uncertain
0.045
T
BayesDel_noAF
Benign
-0.17
CADD
Benign
20
DANN
Benign
0.97
DEOGEN2
Benign
0.029
T;T;T
Eigen
Benign
-0.48
Eigen_PC
Benign
-0.37
FATHMM_MKL
Benign
0.50
N
LIST_S2
Benign
0.62
T;.;T
M_CAP
Benign
0.064
D
MetaRNN
Benign
0.13
T;T;T
MetaSVM
Uncertain
0.031
D
MutationAssessor
Benign
1.3
.;L;L
PhyloP100
1.2
PrimateAI
Benign
0.30
T
PROVEAN
Benign
-1.9
.;N;N
REVEL
Benign
0.23
Sift
Uncertain
0.0050
.;D;D
Sift4G
Benign
0.11
T;T;T
Polyphen
0.0010
.;B;B
Vest4
0.20, 0.17
MutPred
0.39
Loss of disorder (P = 0.0111);Loss of disorder (P = 0.0111);Loss of disorder (P = 0.0111);
MVP
0.92
MPC
0.079
ClinPred
0.21
T
GERP RS
3.0
PromoterAI
-0.030
Neutral
Varity_R
0.30
gMVP
0.87

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

Other links and lift over

hg19: chr17-3379479; API