rs779888892

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3PP5

The NM_177924.5(ASAH1):c.124A>G(p.Thr42Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000752 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T42M) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

ASAH1
NM_177924.5 missense, splice_region

Scores

Splicing: ADA: 0.9991

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 3.61

Variant links:

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]

ASAH1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr8-18075541-G-A is described in Lovd as [Likely_pathogenic].

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

PP5

Variant 8-18075542-T-C is Pathogenic according to our data. Variant chr8-18075542-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 560955.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}. Variant chr8-18075542-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASAH1	NM_177924.5 link	c.124A>G	p.Thr42Ala	missense_variant, splice_region_variant	Exon 2 of 14	ENST00000637790.2	NP_808592.2	Q13510-1Q53H01A8K0B6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASAH1	ENST00000637790.2 link	c.124A>G	p.Thr42Ala	missense_variant, splice_region_variant	Exon 2 of 14	1	NM_177924.5	ENSP00000490272.1		Q13510-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251460

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461836

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.000111

Hom.:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Spinal muscular atrophy-progressive myoclonic epilepsy syndrome

Uncertain:2

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant in c.124A>G in ASAH1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Thr42Ala variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.002% in gnomAD database. This variant has been reported to the ClinVar database as Uncertain Significance. The amino acid change p.Thr42Ala in ASAH1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Thr at position 42 is changed to a Ala changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance (VUS). -

Sep 01, 2017

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Another missense mutation at the same amino acid (with a different substitution) has been described as disease-causing. 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. -

not provided

Pathogenic:1

Oct 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 42 of the ASAH1 protein (p.Thr42Ala). This variant is present in population databases (rs779888892, gnomAD 0.01%). This missense change has been observed in individual(s) with spinal muscular atrophy (PMID: 27026573, 28733637, 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: 560955). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.086

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

T;T;T;.;T;T;T;T;T;.;.;.;.;T;T;T;T;T;.;T;T

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

.;D;D;D;D;D;D;D;D;D;D;D;T;D;D;T;D;D;D;D;D

M_CAP

Uncertain

0.091

MetaRNN

Benign

0.37

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.20

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-2.1

.;N;N;N;.;.;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.

REVEL

Uncertain

0.32

Sift

Benign

0.33

.;T;T;T;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.

Sift4G

Benign

0.56

.;T;T;T;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;.

Polyphen

0.20

B;B;P;B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.59, 0.57, 0.57, 0.64

MutPred

0.24

Loss of phosphorylation at T42 (P = 0.0137);Loss of phosphorylation at T42 (P = 0.0137);Loss of phosphorylation at T42 (P = 0.0137);.;.;Loss of phosphorylation at T42 (P = 0.0137);Loss of phosphorylation at T42 (P = 0.0137);Loss of phosphorylation at T42 (P = 0.0137);Loss of phosphorylation at T42 (P = 0.0137);Loss of phosphorylation at T42 (P = 0.0137);Loss of phosphorylation at T42 (P = 0.0137);.;.;Loss of phosphorylation at T42 (P = 0.0137);Loss of phosphorylation at T42 (P = 0.0137);Loss of phosphorylation at T42 (P = 0.0137);Loss of phosphorylation at T42 (P = 0.0137);Loss of phosphorylation at T42 (P = 0.0137);.;.;.;

MVP

0.89

MPC

0.0088

ClinPred

0.97

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.52

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.98

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over