rs543697946

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_177924.5(ASAH1):c.997C>T(p.Arg333Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,614,056 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. R333G) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ASAH1
NM_177924.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

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 18 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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr8-18059385-G-C is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.976

PP5

Variant 8-18059385-G-A is Pathogenic according to our data. Variant chr8-18059385-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 812490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASAH1	NM_177924.5 linkuse as main transcript	c.997C>T	p.Arg333Cys	missense_variant	12/14	ENST00000637790.2	NP_808592.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASAH1	ENST00000637790.2 linkuse as main transcript	c.997C>T	p.Arg333Cys	missense_variant	12/14	1	NM_177924.5	ENSP00000490272	P2	Q13510-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74320

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Farber lipogranulomatosis

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

literature only

Medical Affairs, Dicerna Pharmaceuticals

Jun 19, 2019

Variant c.997C>T is likely pathogenic based on the following rationale. Variant c.997C>T has been identified in 2 patients diagnosed with Farber disease from unrelated families. Kim et al., 2016, DOI: 10.1002/ajmg.a.37846 is an infant with characteristic clinical features of Type 1 Farber disease (Gene Reviews; https://www.ncbi.nlm.nih.gov/books/NBK488189/). Whole exome sequencing was conducted and compound heterozygous variants were identified in the ASAH1 gene, c.703G>C and c.997C>T. When analyzed using public databases (dbSNP build 137; 1000 Genomes Project release 10.31.2012; NHLBI Exome Sequencing Project), variants were determined to be rare with pathogenic consequences according to Polyphen and SIFT analyses. Variant c.997C>T has also been identified in a second Farber disease patient described in Cozma et al., 2017, DOI:10.1038/s41598-017-06604-2. The patient was a newborn with homozygous c.997C>T variants in the ASAH1 gene. Additional ceramide biomarker testing was completed in this patient along with 2 additional newborn patients diagnosed with Farber disease demonstrating C26:0 levels were significantly higher in this cohort compared to controls. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 06, 2022

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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: 812490). This variant is also known as c.1045C>T(p.Arg349Cys). This missense change has been observed in individuals with Farber disease (PMID: 27411168, 28733637). This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 333 of the ASAH1 protein (p.Arg333Cys). This variant disrupts the p.Arg333 amino acid residue in ASAH1. Other variant(s) that disrupt this residue have been observed in individuals with ASAH1-related conditions (PMID: 24355074, 28733637), which suggests that this may be a clinically significant amino acid residue. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

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

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.36

MetaRNN

Pathogenic

0.98

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

MetaSVM

Uncertain

0.70

MutationAssessor

Pathogenic

3.4

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

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-7.3

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

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.96, 0.98, 0.97, 0.96

MutPred

0.86

Loss of glycosylation at P336 (P = 0.0411);Loss of glycosylation at P336 (P = 0.0411);.;.;.;.;.;.;.;.;.;.;.;.;

MVP

0.98

MPC

0.0093

ClinPred

1.0

GERP RS

5.5

Varity_R

0.94

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.32

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.32

Position offset: -5

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