8-18064501-T-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_177924.5(ASAH1):c.413A>T(p.Glu138Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000211 in 1,419,070 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. E138G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_177924.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ASAH1 | NM_177924.5 | c.413A>T | p.Glu138Val | missense_variant | 6/14 | ENST00000637790.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASAH1 | ENST00000637790.2 | c.413A>T | p.Glu138Val | missense_variant | 6/14 | 1 | NM_177924.5 | P2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000425 AC: 1AN: 235120Hom.: 0 AF XY: 0.00000784 AC XY: 1AN XY: 127522
GnomAD4 exome AF: 0.00000211 AC: 3AN: 1419070Hom.: 0 Cov.: 28 AF XY: 0.00000424 AC XY: 3AN XY: 707666
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 08, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 138 of the ASAH1 protein (p.Glu138Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Farber lipogranulomatosis (PMID: 10610716, 11241842, 32449975, 34240417). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 92). 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 ASAH1 protein function. Experimental studies have shown that this missense change affects ASAH1 function (PMID: 10610716). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 15, 2019 | Reported in a patient with Farber disease in published literature (Li et al., 1999); study did not specify specific clinical information or if a second variant in ASAH1 was identified. Published functional studies demonstrate a damaging effect, resulting in loss of enzymatic activity (Li et al., 1999). Not observed at a significant frequency in large population cohorts (Lek et al., 2016). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. - |
Farber lipogranulomatosis Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1999 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at