rs786204652
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000049.4(ASPA):c.32del(p.Ile11AsnfsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
ASPA
NM_000049.4 frameshift
NM_000049.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.62
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 18 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 153 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 17-3476190-AT-A is Pathogenic according to our data. Variant chr17-3476190-AT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-3476190-AT-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ASPA | NM_000049.4 | c.32del | p.Ile11AsnfsTer15 | frameshift_variant | 1/6 | ENST00000263080.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASPA | ENST00000263080.3 | c.32del | p.Ile11AsnfsTer15 | frameshift_variant | 1/6 | 1 | NM_000049.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251376Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135870
GnomAD3 exomes
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135870
Gnomad AFR exome
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GnomAD4 exome Cov.: 31
GnomAD4 exome
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31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
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32
Bravo
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Spongy degeneration of central nervous system Pathogenic:2
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Nov 06, 2014 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 1996 | - - |
Canavan Disease, Familial Form Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 23, 2022 | Variant summary: ASPA c.32delT (p.Ile11AsnfsX15) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251376 control chromosomes. c.32delT has been reported in the literature in individuals affected with Canavan Disease (example, Kaul_1996). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at