chr8-18064458-T-G

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PM2PP5_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. 16/26 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. K152K) has been classified as Uncertain significance.

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 criteria provided, multiple submitters, no conflicts P:5U:1

Conservation

PhyloP100: 1.30

Publications

12 publications found

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 Gene-Disease associations (from GenCC):

ASAH1-related sphingolipidosis
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Farber lipogranulomatosis
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
spinal muscular atrophy-progressive myoclonic epilepsy syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P

ASAH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

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 Pathogenic. ClinVar VariationId is 180643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
ASAH1	NM_177924.5 link	c.456A>C	p.Lys152Asn	missense_variant, splice_region_variant	Exon 6 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.456A>C	p.Lys152Asn	missense_variant, splice_region_variant	Exon 6 of 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

GnomAD2 exomes

AF:

0.0000576

AC:

AN:

243106

AF XY:

0.0000304

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 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

African (AFR)

AF:

0.00

AC:

AN:

31866

American (AMR)

AF:

0.000180

AC:

AN:

44350

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25592

East Asian (EAS)

AF:

0.00

AC:

AN:

39186

South Asian (SAS)

AF:

0.00

AC:

AN:

84456

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52878

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5634

European-Non Finnish (NFE)

AF:

0.000114

AC:

121

AN:

1058978

Other (OTH)

AF:

0.000137

AC:

AN:

58384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.432

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41456

American (AMR)

AF:

0.000131

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

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

Dec 01, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jan 01, 2017

Care4Rare-SOLVE, CHEO

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

This variant was found in a compound heterozygous state NM_004315.4:c.458A>G. -

Jul 01, 2019

Medical Affairs, Dicerna Pharmaceuticals

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:literature only

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. -

not provided

Pathogenic:2

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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; internal data). 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. -

Aug 07, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis is inconclusive as to whether the variant alters gene splicing; however RNA studies demonstrate in-frame skipping of exon 6 (PMID: 24164096); This variant is associated with the following publications: (PMID: 25847462, 30029679, 25046240, 26526000, 27647482, 27026573, 28251733, 28733637, 33798445, 34426522, 28721829, 36325744, 24164096) -

ASAH1-related disorders

Pathogenic:1

Mar 01, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

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;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

PhyloP100

1.3

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

Mutation Taster

=7/93

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over