chr8-18064501-T-A

Variant names:

• chr8-18064501-T-A
• rs137853594
• NM_177924.5:c.413A>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_177924.5(ASAH1):​c.413A>T​(p.Glu138Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000211 in 1,419,070 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E138G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ASAH1 NM_177924.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.42
• Publications: 8 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 18 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, 10 uncertain in NM_177924.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-18064501-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1687065.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 8-18064501-T-A is Pathogenic according to our data. Variant chr8-18064501-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 92.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASAH1	NM_177924.5	c.413A>T	p.Glu138Val	missense_variant	Exon 6 of 14	ENST00000637790.2	NP_808592.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASAH1	ENST00000637790.2	c.413A>T	p.Glu138Val	missense_variant	Exon 6 of 14	1	NM_177924.5	ENSP00000490272.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000425 AC: 1 AN: 235120 AF XY: 0.00000784

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000295

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000211 AC: 3 AN: 1419070 Hom.: 0 Cov.: 28 AF XY: 0.00000424 AC XY: 3 AN XY: 707666

African (AFR) AF: 0.00 AC: 0 AN: 32132

American (AMR) AF: 0.0000226 AC: 1 AN: 44214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25638

East Asian (EAS) AF: 0.00 AC: 0 AN: 38880

South Asian (SAS) AF: 0.00 AC: 0 AN: 84342

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5672

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1076654

Other (OTH) AF: 0.00 AC: 0 AN: 58926

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Apr 03, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect, resulting in loss of enzymatic activity (PMID: 10610716, 11241842); Reported in a patient with Farber disease in published literature; study did not specify specific clinical information or if a second variant in ASAH1 was identified (PMID: 10610716); Reported along with a second variant in the ASAH1 gene in multiple patients with Farber disease in the published literature; but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (PMID: 11241842, 30815900, 32449975, 34240417); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25525159, 11241842, 32449975, 30815900, 34240417, 10610716) -

Sep 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ASAH1 protein function. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects ASAH1 function (PMID: 10610716). ClinVar contains an entry for this variant (Variation ID: 92). This missense change has been observed in individual(s) with Farber lipogranulomatosis (PMID: 10610716, 11241842, 32449975, 34240417). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 138 of the ASAH1 protein (p.Glu138Val). -

Farber lipogranulomatosis Pathogenic:1

Dec 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.76	D;D;.;T;T;T;.;.;.;T;T;T;T;T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;D;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.077	D
MutationAssessor	Pathogenic	3.1	M;M;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		7.4
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-6.2	.;D;D;.;.;.;.;.;D;.;.;.;.;.
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	.;D;D;.;.;.;.;.;D;.;.;.;.;.
Sift4G	Pathogenic	0.0010	.;D;D;.;.;.;.;.;D;.;.;.;.;.
Polyphen		1.0	D;D;D;.;.;.;.;.;.;.;.;.;.;.
Vest4		1.0, 0.99, 0.99
MutPred		0.88		Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);.;.;.;.;.;.;.;.;.;.;.;Loss of helix (P = 0.1299);
MVP		0.86
MPC		0.011
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.98
gMVP		0.98
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.24		Position offset: 30

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

Other links and lift over

dbSNP: rs137853594; hg19: chr8-17922010;