8-18059385-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_177924.5(ASAH1):c.997C>G(p.Arg333Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000204 in 1,614,174 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 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

ASAH1
NM_177924.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5U:3

Conservation

PhyloP100: 6.01

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a mutagenesis_site Mildly decreased autocatalytic processing. Loss of ceramidase activity. (size 0) in uniprot entity ASAH1_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.958

PP5

Variant 8-18059385-G-C is Pathogenic according to our data. Variant chr8-18059385-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 585439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-18059385-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASAH1	NM_177924.5 link	c.997C>G	p.Arg333Gly	missense_variant	Exon 12 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.997C>G	p.Arg333Gly	missense_variant	Exon 12 of 14	1	NM_177924.5	ENSP00000490272.1		Q13510-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251460

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000392

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000198

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000313

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000827

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000959

Hom.:

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000576

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:3

Uncertain significance, flagged submission	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, flagged submission	clinical testing	Athena Diagnostics	Apr 12, 2018	- -
Uncertain significance, flagged submission	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 08, 2023	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. This variant disrupts the p.Arg333 amino acid residue in ASAH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27411168, 28733637). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 585439). This variant is also known as p.Arg349Gly. This missense change has been observed in individuals with Farber disease (PMID: 24355074, 28733637). This variant is present in population databases (rs543697946, gnomAD 0.04%). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 333 of the ASAH1 protein (p.Arg333Gly). -

Farber lipogranulomatosis

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The ASAH1 c.997C>G p.Arg333Gly variant has been reported in heterozygous state in unrelated families affected with Farber lipogranulomatosis (Bashyam et. al., 2014; Yu. et al., 2018). Experimental studies have shown protein structural analysis on mutated amino acid sequence using HANSA and it is predicted that this change in sequence results in disruption in the conformation of the catalytic triad. (Bashyam et. al., 2014). This variant has been reported to the ClinVar database as Pathogenic, Likely Pathogenic and Variant of Uncertain Significance (VUS). It is reported with allele frequency of 0.006% in gnomAD database. The amino acid Arg at position 333 is changed to a Gly changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg333Gly in ASAH1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	literature only	Medical Affairs, Dicerna Pharmaceuticals	Jun 19, 2019	Published data sheds additional light on variant c.997C>G suggesting the status be updated from uncertain significance to pathogenic. Four children from 3 unrelated families have been diagnosed with Farber disease associated with variant c.997C>G. Patient 1 discussed in Bashyam et al., 2014, doi: 10.1111/cge.12316, was diagnosed with Farber disease due to symptoms characteristic of Farber disease Type 1 (Gene Reviews; https://www.ncbi.nlm.nih.gov/books/NBK488189/). The child has compound heterozygous variants in the ASAH1 gene. Skin biopsy showed diffuse fibroblastic proliferation with diffuse chronic inflammatory cell infiltrates in the dermis with fat and foamy macrophages present in-between the fibroblasts which is characteristic of Farber disease. Protein structural analysis using HANSA was performed for the mutated amino acid sequence. It is predicted this change in sequence results in disruption in the conformation of the catalytic triad. Additionally, 2 siblings from a second unrelated family were were described in Bashyam et al., 2014, with Type 1 Farber disease. These sisters inherited the c.997C>G variant from their parents according to biparental segregation. Lastly, a fourth unrelated Farber disease patient was described in Cozma et al., 2017, DOI:10.1038/s41598-017-06604-2. In this patient, ceramide biomarker C26:0 was measured in samples from 10 Farber patients and 2 SMA-PME patients. It was demonstrated within this group that C26:0 Isoform 1 levels were significanly higher than the control group verifying the presence of Farber disease. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	Mar 14, 2024	- -

Abnormality of metabolism/homeostasis

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

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

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.97

.;D;D;D;D;.;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.39

MetaRNN

Pathogenic

0.96

D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.70

MutationAssessor

Pathogenic

3.4

M;M;.;.;.;.;.;.;.;.;.;.;.;.

PrimateAI

Benign

0.45

PROVEAN

Pathogenic

-6.2

.;D;D;D;.;.;.;.;.;.;.;.;.;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

.;D;D;D;.;.;.;.;.;.;.;.;.;D

Sift4G

Pathogenic

0.0

.;D;D;D;.;.;.;.;.;.;.;.;.;D

Polyphen

1.0

D;D;D;D;.;.;.;.;.;.;.;.;.;.

Vest4

0.93, 0.95, 0.93

MutPred

0.89

Loss of stability (P = 0.0392);Loss of stability (P = 0.0392);.;.;.;.;.;.;.;.;.;.;.;.;

MVP

0.98

MPC

0.0061

ClinPred

0.95

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.97

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

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