8-18064501-T-C

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_177924.5(ASAH1):​c.413A>G​(p.Glu138Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. E138V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASAH1 NM_177924.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.42
• Publications: 0 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 12 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-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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962
• PP5: Variant 8-18064501-T-C is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASAH1	NM_177924.5	c.413A>G	p.Glu138Gly	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>G	p.Glu138Gly	missense_variant	Exon 6 of 14	1	NM_177924.5	ENSP00000490272.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Farber lipogranulomatosis Pathogenic:1

May 20, 2022

Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.461A>G variant is not present in publicly available population databases like 1000 Genomes, Exome Variant Server (EVS), Exome Aggregation Consortium (ExAC), Genome Aggregation Database (gnomAD) and dbSNP. The variant is not present in Indian Exome Database and in our in-house exome database. The variant was not previously reported to ClinVar, Human Genome Mutation Database (HGMD) and/or OMIM databases in any affected individuals. In-silico pathogenicity prediction programs like SIFT, PolyPhen-2, MutationTaster2, CADD, Varsome, InterVar etc. predicted this variant to be likely deleterious. The variant is located in a dense mutational hotspot region of the gene where other pathogenic missense variants has been identified and reported. An alternative variant in the same position (c.461A>T, p.Glu154Val) was previously reported to ClinVar (Accession: VCV000000092.2) and HGMD (ID: CM993321) as pathogenic/likely pathogenic in association with Farber disease (PMID: 10610716).

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.80	D;D;.;T;T;T;.;.;.;T;T;T;T;T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.68
LIST_S2	Benign	0.0	.;D;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.021	D
MutationAssessor	Pathogenic	3.1	M;M;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		7.4
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.0	.;D;D;.;.;.;.;.;D;.;.;.;.;.
Sift	Pathogenic	0.0	.;D;D;.;.;.;.;.;D;.;.;.;.;.
Sift4G	Pathogenic	0.0	.;D;D;.;.;.;.;.;D;.;.;.;.;.
Vest4		0.0
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.91
gMVP		0.98
Mutation Taster		=5/95	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs137853594; hg19: chr8-17922010;