rs145873635

Positions:

chr8-18075541-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong

The ENST00000637790.2(ASAH1):c.125C>T(p.Thr42Met) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000118 in 1,613,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. T42A) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

ASAH1
ENST00000637790.2 missense, splice_region

Scores

Splicing: ADA: 0.9929

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 4.44

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 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, 7 uncertain in ENST00000637790.2

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: 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}.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.77

PP5

Variant 8-18075541-G-A is Pathogenic according to our data. Variant chr8-18075541-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 35544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-18075541-G-A is described in Lovd as [Likely_pathogenic]. Variant chr8-18075541-G-A is described in Lovd as [Pathogenic]. Variant chr8-18075541-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASAH1	NM_177924.5 linkuse as main transcript	c.125C>T	p.Thr42Met	missense_variant, splice_region_variant	2/14	ENST00000637790.2	NP_808592.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASAH1	ENST00000637790.2 linkuse as main transcript	c.125C>T	p.Thr42Met	missense_variant, splice_region_variant	2/14	1	NM_177924.5	ENSP00000490272	P2	Q13510-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251458

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461788

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000483

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Spinal muscular atrophy-progressive myoclonic epilepsy syndrome

Pathogenic:4Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 03, 2017	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.T42M in ASAH1 (NM_177924.5) has been reported previously in affected patients (Zhou et al). Functional studies reveal a damaging effect. The p.T42M variant isobserved in 2/16,256 (0.0123%) alleles from individuals of African background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between threonine and methionine. 3 variants within 6 amino acid positions of the variant p.T42M have been shown to be pathogenic, while none have been shown to be benign. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 13, 2012	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PM3_Strong+PP1+PP4 -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 06, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 30, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 42 of the ASAH1 protein (p.Thr42Met). This variant is present in population databases (rs145873635, gnomAD 0.02%). This missense change has been observed in individual(s) with with spinal muscular atrophy and progressive myoclonic epilepsy (PMID: 22703880, 25578555, 25847462, 27723502). 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: 35544). 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 disruptive. For these reasons, this variant has been classified as Pathogenic. -

ASAH1-related disorders

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 12, 2019	The ASAH1 c.173C>T (p.Thr58Met) variant is a missense variant that has been reported in four studies, in which it is found in a total of 10 individuals with spinal muscular atrophy associated with progressive myoclonic epilepsy, including in eight in a homozygous state and in two in a compound heterozygous state (Zhou et al. 2012; Rubboli et al. 2015; GirÃ¡ldez et al. 2015; Yildiz et al. 2018). This variant segregated with disease in two families. The p.Thr58Met variant was absent from 95 control subjects but is reported at a frequency of 0.000196 in the African population of the Genome Aggregation Database. Transient expression of the p.Thr58Met cDNA into fibroblasts derived from an individual with Farber disease demonstrated that the acid-ceramidase activity was 32% of the wild type cDNA activity. Although there was no effect on the level of the precursor form or its processing, the Î±-subunit amount was mildly lower than the Î²-subunit amount (Zhou et al. 2012). Based on the collective evidence and application of the ACMG criteria, the p.Thr58Met variant is classified as pathogenic for ASAH1-related disorders. -
Likely pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 26, 2022	The ASAH1 c.173C>T variant is predicted to result in the amino acid substitution p.Thr58Met. This variant (also known as c.125C>T, p.Thr42Met in transcript NM_177924.5) was reported in homozygous and compound heterozygous state in several individuals with Spinal muscular atrophy associated with progressive myoclonic epilepsy (Yildiz et al. 2017. PubMed ID: 29169047; Zhou et al. 2012. PubMed ID: 22703880; Akarsu et al. 2016. PubMed ID: 27723502; Giráldez et al. 2014. PubMed ID: 25578555; Rubboli et al. 2015. PubMed ID: 25847462). Functional expression studies of the c.173C>T mutant cDNA in Farber fibroblasts showed that acid-ceramidase activity was only 32% of that generated by normal cDNA, however this reduced activity was able to normalize the ceramide level in Farber cells. Knockdown of the ASAH1 ortholog in zebrafish led to a marked loss of motor-neuron axonal branching, a loss that is associated with increased apoptosis in the spinal cord and authors assume this could be the pathogenic mechanism underlying the CNS involvement in deficient cells in case of enzyme activity reduction in this variant (Zhou et al. 2012. PubMed ID: 22703880). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-17933050-G-A). This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Uncertain

0.020

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.031

.;T

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.44

T;T

M_CAP

Pathogenic

0.36

MetaRNN

Pathogenic

0.77

D;D

MetaSVM

Uncertain

0.076

MutationTaster

Benign

1.0

D;D;D;D;D

PROVEAN

Benign

-2.1

N;.

REVEL

Uncertain

0.62

Sift

Uncertain

0.012

D;.

Sift4G

Benign

0.21

T;.

Vest4

0.63

MVP

0.86

ClinPred

0.94

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.73

SpliceAI score (max)

0.0

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