8-18061425-A-G

Position:

chr8-18061425-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The ENST00000637790.2(ASAH1):c.737T>C(p.Val246Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.966 in 1,612,938 control chromosomes in the GnomAD database, including 758,609 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.88 ( 60692 hom., cov: 33)

Exomes 𝑓: 0.98 ( 697917 hom. )

Consequence

ASAH1
ENST00000637790.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 2.96

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 Benign. Variant got -18 ACMG points.

PM1

In a chain Acid ceramidase subunit beta (size 252) in uniprot entity ASAH1_HUMAN there are 37 pathogenic changes around while only 6 benign (86%) in ENST00000637790.2

BP4

Computational evidence support a benign effect (MetaRNN=5.797227E-7).

BP6

Variant 8-18061425-A-G is Benign according to our data. Variant chr8-18061425-A-G is described in ClinVar as [Benign]. Clinvar id is 259283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-18061425-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.985 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASAH1	NM_177924.5 linkuse as main transcript	c.737T>C	p.Val246Ala	missense_variant	10/14	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.737T>C	p.Val246Ala	missense_variant	10/14	1	NM_177924.5	ENSP00000490272	P2	Q13510-1

Frequencies

GnomAD3 genomes

AF:

0.878

AC:

133534

AN:

152090

Hom.:

60671

Cov.:

show subpopulations

Gnomad AFR

AF:

0.620

Gnomad AMI

AF:

0.999

Gnomad AMR

AF:

0.946

Gnomad ASJ

AF:

0.996

Gnomad EAS

AF:

0.876

Gnomad SAS

AF:

0.963

Gnomad FIN

AF:

0.964

Gnomad MID

AF:

0.956

Gnomad NFE

AF:

0.991

Gnomad OTH

AF:

0.913

GnomAD3 exomes

AF:

0.948

AC:

238477

AN:

251432

Hom.:

114213

AF XY:

0.955

AC XY:

129822

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.609

Gnomad AMR exome

AF:

0.972

Gnomad ASJ exome

AF:

0.994

Gnomad EAS exome

AF:

0.869

Gnomad SAS exome

AF:

0.963

Gnomad FIN exome

AF:

0.967

Gnomad NFE exome

AF:

0.991

Gnomad OTH exome

AF:

0.963

GnomAD4 exome

AF:

0.976

AC:

1425052

AN:

1460730

Hom.:

697917

Cov.:

AF XY:

0.976

AC XY:

709507

AN XY:

726806

show subpopulations

Gnomad4 AFR exome

AF:

0.609

Gnomad4 AMR exome

AF:

0.969

Gnomad4 ASJ exome

AF:

0.994

Gnomad4 EAS exome

AF:

0.898

Gnomad4 SAS exome

AF:

0.961

Gnomad4 FIN exome

AF:

0.968

Gnomad4 NFE exome

AF:

0.992

Gnomad4 OTH exome

AF:

0.953

GnomAD4 genome

AF:

0.878

AC:

133604

AN:

152208

Hom.:

60692

Cov.:

AF XY:

0.879

AC XY:

65396

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.620

Gnomad4 AMR

AF:

0.947

Gnomad4 ASJ

AF:

0.996

Gnomad4 EAS

AF:

0.876

Gnomad4 SAS

AF:

0.963

Gnomad4 FIN

AF:

0.964

Gnomad4 NFE

AF:

0.991

Gnomad4 OTH

AF:

0.914

Alfa

AF:

0.968

Hom.:

157476

Bravo

AF:

0.862

TwinsUK

AF:

0.993

AC:

3683

ALSPAC

AF:

0.992

AC:

3822

ESP6500AA

AF:

0.624

AC:

2749

ESP6500EA

AF:

0.991

AC:

8522

ExAC

AF:

0.943

AC:

114493

Asia WGS

AF:

0.902

AC:

3137

AN:

3478

EpiCase

AF:

0.989

EpiControl

AF:

0.990

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 94% of total chromosomes in ExAC -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:4

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Farber lipogranulomatosis

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Spinal muscular atrophy-progressive myoclonic epilepsy syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Farber lipogranulomatosis;C1834569:Spinal muscular atrophy-progressive myoclonic epilepsy syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 30, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.045

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.84

DEOGEN2

Benign

0.39

T;T;T;.;T;T;T;T;T;T;T;.;.;.;.;T

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.050

.;T;T;T;T;.;T;T;T;T;T;T;T;T;T;T

MetaRNN

Benign

5.8e-7

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-2.4

N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

P;P;P;P;P

PrimateAI

Benign

0.38

PROVEAN

Benign

2.8

.;N;N;N;.;.;.;.;.;.;.;.;.;.;N;.

REVEL

Benign

0.26

Sift

Benign

1.0

.;T;T;T;.;.;.;.;.;.;.;.;.;.;T;.

Sift4G

Benign

1.0

.;T;T;T;.;.;.;.;.;.;.;.;.;.;T;.

Polyphen

0.0

B;B;B;B;.;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.042, 0.032, 0.046

MPC

0.0028

ClinPred

0.0082

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.035

gMVP

0.59

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