8-18064458-T-G

Position:

chr8-18064458-T-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM1PM2PP5_Very_StrongBP4

The NM_177924.5(ASAH1):c.456A>C(p.Lys152Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000092 in 1,553,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/25 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000098 ( 0 hom. )

Consequence

ASAH1
NM_177924.5 missense, splice_region

Scores

Splicing: ADA: 0.1912

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5U:1

Conservation

PhyloP100: 1.30

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:

ASAH1 (HGNC:):

ASAH1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1

In a chain Acid ceramidase subunit beta (size 252) in uniprot entity ASAH1_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_177924.5

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 8-18064458-T-G is Pathogenic according to our data. Variant chr8-18064458-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 180643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-18064458-T-G is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.18940812). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASAH1	NM_177924.5 linkuse as main transcript	c.456A>C	p.Lys152Asn	missense_variant, splice_region_variant	6/14	ENST00000637790.2	NP_808592.2	Q13510-1Q53H01A8K0B6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASAH1	ENST00000637790.2 linkuse as main transcript	c.456A>C	p.Lys152Asn	missense_variant, splice_region_variant	6/14	1	NM_177924.5	ENSP00000490272.1		Q13510-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000576

AC:

AN:

243106

Hom.:

AF XY:

0.0000304

AC XY:

AN XY:

131542

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000146

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000470

Gnomad NFE exome

AF:

0.0000734

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000978

AC:

137

AN:

1401324

Hom.:

Cov.:

AF XY:

0.0000900

AC XY:

AN XY:

699890

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000180

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:

0.000114

Gnomad4 OTH exome

AF:

0.000137

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000774

Hom.:

Bravo

AF:

0.0000453

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Spinal muscular atrophy-progressive myoclonic epilepsy syndrome

Pathogenic:2Uncertain:1

Pathogenic, criteria provided, single submitter	literature only	Medical Affairs, Dicerna Pharmaceuticals	Jul 01, 2019	Although variant c.456A>C has been noted in Clinvar as a variant with conflicting evidence, there is significant new evidence that supports the clinical pathogenicity of c.456A>C. In addition to the patient described by Gan et al., 2015, DOI: 10.1016/j.nmd.2015.09.007, this variant has been described in 4 additional patients from unrelated families and published in Cozma et al., 2017, DOI:10.1038/s41598-017-06604-2, Dyment et al., 2014, doi: 10.1111/cge.12307, Kernohan et al., 2017, doi:10.1002/humu.23211, and Rubboli et al., 2017, doi: 10.1111/epi.12977. In the patient described in Gan et al., 2015, histological studies were completed demonstrating the presence of zebra bodies that are characteristic of acid ceramidase deficiency. Additionally, functional studies have been conducted using this variant. Acid ceramidase enzyme activity was measured in this patient's and mother's fibroblasts. The patient has approximately 15% enzyme activity of controls and the mother has acid ceramidase activity of approximately 50% normal. -
Uncertain significance, no assertion criteria provided	research	Care4Rare-SOLVE, CHEO	Jan 01, 2017	This variant was found in a compound heterozygous state NM_004315.4:c.458A>G. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2014	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 02, 2023	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 152 of the ASAH1 protein (p.Lys152Asn). This variant is present in population databases (rs200455852, gnomAD 0.01%). This missense change has been observed in individual(s) with ASAH1-related conditions (PMID: 24164096, 25847462, 26526000; Invitae). 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: 180643). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 28, 2019	The c.456 A>C variant in the ASAH1 gene has been reported previously, as K152N and K168N, in a few unrelated individuals with spinal muscular atrophy with progressive myoclonic epilepsy who also harbored a second ASAH1 variant (Dyment et al., 2014; Gan et al., 2015; Kernohan et al., 2017). Functional studies of cultured patient-derived fibroblasts demonstrate reduction in both acid ceramidase levels and enzymatic activity (Dymet et al., 2014). The c.456 A>C variant is observed in 5/34116 alleles (0.0147%) from individuals of Latino background in large population cohorts, with no homozygotes observed (Lek et al., 2016). In-silico splice models predict that c.456 A>C may destroy the natural splice donor site of intron 6. However, in the absence of RNA/functional studies, the actual effect of the c.456 A>C change in this individual is unknown. If c.456 A>C does not alter splicing, it will result in the K152N missense change. The K152N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We interpret c.456 A>C as a likely pathogenic variant. -

ASAH1-related disorders

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 2024

The ASAH1 c.504A>C variant is predicted to result in the amino acid substitution p.Lys168Asn. This variant (also known as c.456A>C; p.Lys152Asn) was reported in compound heterozygous state in multiple individuals with spinal muscular atrophy associated with progressive myoclonic epilepsy (Dyment et al. 2014. PubMed ID: 24164096; Gan et al. 2015. PubMed ID: 26526000; Cozma et al. 2017. PubMed ID: 28733637; Kernohan et al. 2017. PubMed ID: 28251733; Rubboli et al. 2015. PubMed ID: 25847462). In a patient who was compound heterozygous for this variant and p.Gly284X, functional studies in cultured fibroblasts showed significantly reduced acid ceramidase enzymatic activity (Dyment et al. 2014. Pubmed ID: 24164096). Experimental studies have shown that this variant disrupts mRNA splicing (Kernohan et al. 2017. Pubmed ID: 28251733). This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.42

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

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.74

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

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.19

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

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.81

L;L;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.21

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

REVEL

Benign

0.24

Sift

Benign

0.42

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

Sift4G

Benign

0.68

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

Polyphen

0.0010

B;B;B;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.21, 0.26, 0.27

MVP

0.82

MPC

0.0029

ClinPred

0.052

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.27

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.19

dbscSNV1_RF

Benign

0.41

SpliceAI score (max)

0.41

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.41

Position offset: -1

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