rs769653717
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000049.4(ASPA):āc.47T>Cā(p.Ile16Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,802 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 (ā ā ). Synonymous variant affecting the same amino acid position (i.e. I16I) has been classified as Likely benign.
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.47T>C | p.Ile16Thr | missense_variant | 1/6 | ENST00000263080.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASPA | ENST00000263080.3 | c.47T>C | p.Ile16Thr | missense_variant | 1/6 | 1 | NM_000049.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251420Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135886
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461802Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727198
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Spongy degeneration of central nervous system Pathogenic:6
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 10, 2022 | The p.Ile16Thr variant in ASPA has been reported in compound heterozygous state with another pathogenic ASPA variant in 3 individuals with Canavan Disease (Kaul 1996 PMID: 8659549, Elpeleg 1999 PMID: 10407784, Zeng 2002 PMID: 12638939). It at least 1 individual, the Ile16Thr variant was confirmed to be in trans. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 550560) and has been identified in 0.002% (2/113756) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies of enzyme activity provide evidence that this variant affects protein function, as its enzymatic activity was 0.4% of the wild type allele (Kaul 1996 PMID: 8659549). Computational prediction tools and conservation analyses do not provide evidence for or against an effect to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Canavan Disease. ACMG/AMP Criteria applied: PM3_Strong, PM2_Supporting, PS3_Moderate. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 01, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 14, 2022 | This missense change has been observed in individual(s) with Canavan disease (PMID: 8659549, 12638939). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ASPA function (PMID: 8659549). 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. ClinVar contains an entry for this variant (Variation ID: 550560). This variant is present in population databases (rs769653717, gnomAD 0.002%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 16 of the ASPA protein (p.Ile16Thr). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 01, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 06, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at