rs786204469
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_000049.4(ASPA):c.820G>A(p.Gly274Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,866 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G274E) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000049.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ASPA | NM_000049.4 | c.820G>A | p.Gly274Arg | missense_variant | 6/6 | ENST00000263080.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASPA | ENST00000263080.3 | c.820G>A | p.Gly274Arg | missense_variant | 6/6 | 1 | NM_000049.4 | P1 | |
ASPA | ENST00000456349.6 | c.820G>A | p.Gly274Arg | missense_variant | 7/7 | 1 | P1 | ||
SPATA22 | ENST00000541913.5 | c.-74+14446C>T | intron_variant | 2 | |||||
SPATA22 | ENST00000570318.1 | c.-74+14645C>T | intron_variant | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152190Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251168Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135766
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461676Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 727144
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152190Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74362
ClinVar
Submissions by phenotype
Spongy degeneration of central nervous system Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 11, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 274 of the ASPA protein (p.Gly274Arg). This variant is present in population databases (rs761064915, gnomAD 0.002%). This missense change has been observed in individuals with Canavan disease (PMID: 7668285, 16138249, 22219087, 27457812). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 188788). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ASPA protein function. Experimental studies have shown that this missense change affects ASPA function (PMID: 22850825). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 17, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 26, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | May 16, 2014 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 28, 2022 | Published functional studies demonstrate G274R results in significantly reduced, but not absent, ASPA activity (Hershfield et al., 2007; Zano et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23233226, 22850825, 7668285, 27457812, 17999961, 17194761, 10407784, 22219087, 17391648, 31839386, 16138249) - |
Canavan Disease, Familial Form Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 10, 2022 | Variant summary: ASPA c.820G>A (p.Gly274Arg) 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 allele was found at a frequency of 8e-06 in 251168 control chromosomes (gnomAD). c.820G>A has been reported in the literature in multiple homozygous individuals affected with Canavan Disease (Shaag_1995, Tacke_2005, Hussain_2012, Cakar_2020). In addition, in one Pakistani family, the variant co-segregated with the disease (Hussain_2012). These data indicate that the variant is very likely to be associated with disease. At least one functional study reports this variant results in decreasing normal aspartoacylase activity and conformational stability (Zano_2013). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at