Genetic Variant ASAH1:p.Val63Leu (chr8-18073263-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The ENST00000314146.10(ASAH1):c.187G>C(p.Val63Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V63I) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ASAH1
ENST00000314146.10 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.03

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

ASAH1-related sphingolipidosis
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Farber lipogranulomatosis
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
spinal muscular atrophy-progressive myoclonic epilepsy syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P

ASAH1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in ENST00000314146.10

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06966573).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000314146.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ASAH1	NM_177924.5	MANE Select	c.126-1873G>C		intron	N/A	NP_808592.2
ASAH1	NM_001127505.3		c.187G>C	p.Val63Leu	missense	Exon 3 of 14	NP_001120977.1
ASAH1	NM_004315.6		c.174-1873G>C		intron	N/A	NP_004306.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ASAH1	ENST00000314146.10	TSL:1	c.187G>C	p.Val63Leu	missense	Exon 3 of 14	ENSP00000326970.10
ASAH1	ENST00000637790.2	TSL:1 MANE Select	c.126-1873G>C		intron	N/A	ENSP00000490272.1
ASAH1	ENST00000381733.9	TSL:1	c.174-1873G>C		intron	N/A	ENSP00000371152.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1407102

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

700098

African (AFR)

AF:

0.00

AC:

AN:

32828

American (AMR)

AF:

0.00

AC:

AN:

41522

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25102

East Asian (EAS)

AF:

0.00

AC:

AN:

39032

South Asian (SAS)

AF:

0.00

AC:

AN:

83038

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52182

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5604

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1069612

Other (OTH)

AF:

0.00

AC:

AN:

58182

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.31

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.0061

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.00016

LIST_S2

Benign

0.25

M_CAP

Benign

0.0086

MetaRNN

Benign

0.070

MetaSVM

Benign

-1.0

PhyloP100

-1.0

PROVEAN

Benign

0.010

REVEL

Benign

0.049

Sift

Benign

0.20

Sift4G

Benign

0.19

Vest4

0.033

MutPred

0.27

Gain of helix (P = 0.2059)

MVP

0.21

ClinPred

0.039

GERP RS

-1.6

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over