rs1555538144
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000049.4(ASPA):c.89T>C(p.Leu30Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
ASPA
NM_000049.4 missense
NM_000049.4 missense
Scores
14
3
2
Clinical Significance
Conservation
PhyloP100: 7.79
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.99
PP5
Variant 17-3476248-T-C is Pathogenic according to our data. Variant chr17-3476248-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 556181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ASPA | NM_000049.4 | c.89T>C | p.Leu30Pro | missense_variant | 1/6 | ENST00000263080.3 | NP_000040.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ASPA | ENST00000263080.3 | c.89T>C | p.Leu30Pro | missense_variant | 1/6 | 1 | NM_000049.4 | ENSP00000263080.2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Spongy degeneration of central nervous system Pathogenic:2Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 22, 2019 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has been reported to affect ASPA protein function (PMID: 28101991). This variant has been observed in the homozygous state in an individual affected with Canavan disease (PMID: 28101991). ClinVar contains an entry for this variant (Variation ID: 556181). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 30 of the ASPA protein (p.Leu30Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Uncertain significance, flagged submission | clinical testing | Counsyl | Jan 17, 2018 | - - |
Canavan Disease, Familial Form Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 11, 2023 | Variant summary: ASPA c.89T>C (p.Leu30Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251468 control chromosomes. c.89T>C has been reported in the literature in at least one homozygous individual affected with Canavan Disease (e.g., Mendes_2017). Experimental evidence evaluating an impact on protein function, found that HEK293 cells transfected with the variant protein displayed <1% enzymatic activity (Mendes_2017). These data indicate that the variant is likely to be associated with disease. Three ClinVar submitters (evaluation after 2014) have cited the variant, with two submitters classifying is as likely pathogenic, and one submitter classifying it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;M;M
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
.;D;D
REVEL
Pathogenic
Sift
Uncertain
.;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
1.0
.;D;D
Vest4
0.96, 0.97
MutPred
Loss of stability (P = 0.024);Loss of stability (P = 0.024);Loss of stability (P = 0.024);
MVP
MPC
0.52
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at