chr8-18075541-G-A

Position:

• chr8-18075541-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_001363743.2(ASAH1):​c.-71C>T variant causes a 5 prime UTR premature start codon gain 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. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: ASAH1 NM_001363743.2 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 0.9929
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 4.44

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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	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	c.125C>T	p.Thr42Met	missense_variant, splice_region_variant	2/14	1	NM_177924.5	ENSP00000490272.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152144 Hom.: 0 Cov.: 32

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: 3 AN: 251458 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135898

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: 14 AN: 1461788 Hom.: 0 Cov.: 30 AF XY: 0.00000963 AC XY: 7 AN XY: 727200

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: 5 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74314

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.: 0

Bravo AF: 0.0000227

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spinal muscular atrophy-progressive myoclonic epilepsy syndrome Pathogenic:4 Other: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; Giráldez 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 α-subunit amount was mildly lower than the β-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	T
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.031	.;T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.44	T;T
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Uncertain	0.076	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	D
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

Other links and lift over

dbSNP: rs145873635; hg19: chr8-17933050;