rs756455049

Positions:

chr8-18062422-A-G

Variant summary

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

The NM_177924.5(ASAH1):c.505T>C(p.Trp169Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ASAH1
NM_177924.5 missense, splice_region

Scores

Splicing: ADA: 0.6723

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 8.94

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 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;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

PP5

Variant 8-18062422-A-G is Pathogenic according to our data. Variant chr8-18062422-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 191340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-18062422-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASAH1	NM_177924.5 linkuse as main transcript	c.505T>C	p.Trp169Arg	missense_variant, splice_region_variant	8/14	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.505T>C	p.Trp169Arg	missense_variant, splice_region_variant	8/14	1	NM_177924.5	ENSP00000490272	P2	Q13510-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251344

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135844

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461728

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727160

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Farber lipogranulomatosis

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 04, 2021	- -
Likely pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Mar 01, 2023	The missense/ splice region variant c.505T>C (p.Trp169Arg) in the ASAH1 gene has been reported previously in compound heterozygous and homozygous states in individuals affected with Farber's Disease. Experimental studies have shown that this missense change affects protein function (Gebai et al., 2018; Moghadam et al., 2019). This variant is reported with the allele frequency (0.0003%) in the gnomAD and novel in the 1000 genome database. It is submitted to ClinVar with varying interpretations as Pathogenic/ Likely Pathogenic. The amino acid Tryptophan at position 169 is changed to an Arginine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. The amino acid change p.Trp169Arg in ASAH1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, flagged submission

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

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

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.85

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

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.98

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

MetaSVM

Uncertain

0.47

MutationAssessor

Pathogenic

3.1

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

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-13

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

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0020

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.98, 0.99, 0.97, 0.98

MutPred

0.86

Loss of catalytic residue at L167 (P = 0.0286);Loss of catalytic residue at L167 (P = 0.0286);.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;

MVP

0.97

MPC

0.0039

ClinPred

1.0

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.93

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.67

dbscSNV1_RF

Benign

0.55

SpliceAI score (max)

0.050

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