8-18062307-T-A
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4BS2
The NM_177924.5(ASAH1):c.620A>T(p.Tyr207Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000631 in 1,614,226 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00048 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00065 ( 2 hom. )
Consequence
ASAH1
NM_177924.5 missense
NM_177924.5 missense
Scores
6
7
6
Clinical Significance
Conservation
PhyloP100: 7.67
Genes affected
ASAH1 (HGNC:735): (N-acylsphingosine amidohydrolase 1) This gene encodes a member of the acid ceramidase family of proteins. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. Processing of this preproprotein generates alpha and beta subunits that heterodimerize to form the mature lysosomal enzyme, which catalyzes the degradation of ceramide into sphingosine and free fatty acid. This enzyme is overexpressed in multiple human cancers and may play a role in cancer progression. Mutations in this gene are associated with the lysosomal storage disorder, Farber lipogranulomatosis, and a neuromuscular disorder, spinal muscular atrophy with progressive myoclonic epilepsy. [provided by RefSeq, Oct 2015]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PM1
In a chain Acid ceramidase subunit beta (size 252) in uniprot entity ASAH1_HUMAN there are 37 pathogenic changes around while only 7 benign (84%) in NM_177924.5
BP4
Computational evidence support a benign effect (MetaRNN=0.39019495).
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ASAH1 | NM_177924.5 | c.620A>T | p.Tyr207Phe | missense_variant | 8/14 | ENST00000637790.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASAH1 | ENST00000637790.2 | c.620A>T | p.Tyr207Phe | missense_variant | 8/14 | 1 | NM_177924.5 | P2 |
Frequencies
GnomAD3 genomes AF: 0.000480 AC: 73AN: 152242Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000346 AC: 87AN: 251454Hom.: 0 AF XY: 0.000331 AC XY: 45AN XY: 135902
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GnomAD4 exome AF: 0.000646 AC: 945AN: 1461866Hom.: 2 Cov.: 31 AF XY: 0.000652 AC XY: 474AN XY: 727232
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GnomAD4 genome AF: 0.000479 AC: 73AN: 152360Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30AN XY: 74506
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:10Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:7
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 12, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 24, 2022 | This sequence change replaces tyrosine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 207 of the ASAH1 protein (p.Tyr207Phe). This variant is present in population databases (rs150268016, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with ASAH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 362377). 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 not expected to disrupt ASAH1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 05, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 30, 2018 | The Y207F variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The Y207F variant is observed in 95/126,696 (0.07%) alleles from individuals of European background (Lek et al., 2016). This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Farber lipogranulomatosis Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 01, 2018 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Childhood epilepsy with centrotemporal spikes Pathogenic:1
Pathogenic, no assertion criteria provided | case-control | Bioinformatics Core, Luxembourg Center for Systems Biomedicine | Jan 01, 2017 | CAADphred>15 - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 13, 2022 | The c.620A>T (p.Y207F) alteration is located in exon 8 (coding exon 8) of the ASAH1 gene. This alteration results from a A to T substitution at nucleotide position 620, causing the tyrosine (Y) at amino acid position 207 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Farber lipogranulomatosis;C1834569:Spinal muscular atrophy-progressive myoclonic epilepsy syndrome Other:1
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;D;.;T;T;T;T;T;T;T;.;.;.;T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
.;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
.;D;D;D;.;.;.;.;.;.;.;.;.;D;.;.
REVEL
Pathogenic
Sift
Benign
.;T;T;T;.;.;.;.;.;.;.;.;.;T;.;.
Sift4G
Benign
.;T;T;T;.;.;.;.;.;.;.;.;.;T;.;.
Polyphen
P;P;D;P;.;.;.;.;.;.;.;.;.;.;.;.
Vest4
0.68, 0.71, 0.68
MVP
0.89
MPC
0.012
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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Score
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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