Variant 8-18062383-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The ENST00000637790.2(ASAH1):c.544C>G(p.Leu182Val) variant causes a missense change. 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 Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. L182L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

ASAH1
ENST00000637790.2 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 4.02

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 Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in ENST00000637790.2

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.974

PP5

Variant 8-18062383-G-C is Pathogenic according to our data. Variant chr8-18062383-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 95.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASAH1	NM_177924.5 linkuse as main transcript	c.544C>G	p.Leu182Val	missense_variant	8/14	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.544C>G	p.Leu182Val	missense_variant	8/14	1	NM_177924.5	ENSP00000490272.1		Q13510-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Farber lipogranulomatosis

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.34

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

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

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

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

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.97

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

MetaSVM

Uncertain

0.67

MutationAssessor

Pathogenic

3.4

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

MutationTaster

Benign

1.0

A;A;A;A;A

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.0

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

REVEL

Pathogenic

0.74

Sift

Pathogenic

0.0

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

Sift4G

Uncertain

0.0070

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

Polyphen

1.0

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

Vest4

0.82, 0.81, 0.81, 0.82

MutPred

0.93

Gain of methylation at K183 (P = 0.0314);Gain of methylation at K183 (P = 0.0314);.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;

MVP

0.95

MPC

0.012

ClinPred

0.99

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.87

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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