rs766257867
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_177924.5(ASAH1):c.536C>T(p.Thr179Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,848 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
ASAH1
NM_177924.5 missense
NM_177924.5 missense
Scores
7
6
1
Clinical Significance
Conservation
PhyloP100: 5.18
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_pathogenic. Variant got 7 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_177924.5
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.842
PP5
?
Variant 8-18062391-G-A is Pathogenic according to our data. Variant chr8-18062391-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 560956.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ASAH1 | NM_177924.5 | c.536C>T | p.Thr179Ile | missense_variant | 8/14 | ENST00000637790.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ASAH1 | ENST00000637790.2 | c.536C>T | p.Thr179Ile | missense_variant | 8/14 | 1 | NM_177924.5 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
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Cov.:
32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251406Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135880
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461848Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727218
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Spinal muscular atrophy-progressive myoclonic epilepsy syndrome Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | literature only | Medical Affairs, Dicerna Pharmaceuticals | Jun 18, 2019 | It is our recommendation to update the status of variant c.536C>T from VUS to pathogenic due to recent publications discussing the pathogenicity of this variant. Multiple patients have been diagnosed with SMA-PME who carry the c.546C>T variant. In Sathe et al., 2014, DOI: 10.1016/j.ymgme.2013.12.226, the patient presented with SMA-PME according to Gene Reviews (https://www.ncbi.nlm.nih.gov/books/NBK488189/). Compound heterozygous variants, c.536C>T and c.125A>G, were identified in the patient using whole genome sequencing. Variant c.536C>T has been identified in an additional unrelated patients diagnosed with SMA-PME including a patient listed in Clinvar and identified at Baylor College of Medicine (SCV000807360.1) and 1 patient published in Cozma et al., 2017, DOI:10.1038/s41598-017-06604-2. Ceramide biomarker analysis in this patient (Cozma et al., 2017) along with 9 additional Farber disease patients and 2 SMA-PME patients demonstrated that C26:0 levels were significantly higher in Farber patients and SMA-PME patients compared to controls. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 01, 2017 | Likely pathogenicity based on finding it in trans with another missense mutation in a 14-year-old female with progressive cognitive impairment, flaccid proximal limb weakness with childhood onset, hyperreflexia, seizure disorder, dystonia, myoclonus, mild cerebral atrophy. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Pathogenic
DEOGEN2
Pathogenic
D;D;D;.;T;T;T;T;T;T;T;.;.;.;T;T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;M;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
Polyphen
D;D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4
0.70, 0.70, 0.68, 0.69
MutPred
Loss of ubiquitination at K183 (P = 0.1016);Loss of ubiquitination at K183 (P = 0.1016);.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP
0.96
MPC
0.011
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
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Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at