Variant chr8-18061458-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate

The NM_177924.5(ASAH1):c.704G>T(p.Gly235Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,457,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ASAH1
NM_177924.5 missense, splice_region

Scores

Splicing: ADA: 0.9998

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.36

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:

ASAH1 (HGNC:):

ASAH1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 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, 0.985

PP5

Variant 8-18061458-C-A is Pathogenic according to our data. Variant chr8-18061458-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3066142.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASAH1	NM_177924.5 linkuse as main transcript	c.704G>T	p.Gly235Val	missense_variant, splice_region_variant	10/14	ENST00000637790.2	NP_808592.2	Q13510-1Q53H01A8K0B6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASAH1	ENST00000637790.2 linkuse as main transcript	c.704G>T	p.Gly235Val	missense_variant, splice_region_variant	10/14	1	NM_177924.5	ENSP00000490272.1		Q13510-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1457858

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725582

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:

0.00000271

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Farber lipogranulomatosis

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

MVZ Medizinische Genetik Mainz

Apr 14, 2023

ACMG Criteria: PM3,PM5,PP3_MOD,PM2_SUP -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

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

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.97

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

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.99

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

MetaSVM

Uncertain

0.58

MutationAssessor

Uncertain

2.8

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

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-8.3

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

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

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

Sift4G

Uncertain

0.0050

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

Polyphen

0.99

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

Vest4

0.94, 0.94, 0.92

MutPred

0.88

Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);.;.;.;.;.;.;.;.;.;.;.;.;.;.;

MVP

0.97

MPC

0.010

ClinPred

1.0

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.96

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

SpliceAI score (max)

0.040

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