8-18069818-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_177924.5(ASAH1):c.277A>G(p.Ile93Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.475 in 1,562,986 control chromosomes in the GnomAD database, including 181,906 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.43 ( 14946 hom., cov: 32)

Exomes 𝑓: 0.48 ( 166960 hom. )

Consequence

ASAH1
NM_177924.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.77

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.8589424E-6).

BP6

Variant 8-18069818-T-C is Benign according to our data. Variant chr8-18069818-T-C is described in ClinVar as [Benign]. Clinvar id is 197389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-18069818-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.518 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASAH1	NM_177924.5 link	c.277A>G	p.Ile93Val	missense_variant	Exon 4 of 14	ENST00000637790.2	NP_808592.2	Q13510-1Q53H01A8K0B6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASAH1	ENST00000637790.2 link	c.277A>G	p.Ile93Val	missense_variant	Exon 4 of 14	1	NM_177924.5	ENSP00000490272.1		Q13510-1

Frequencies

GnomAD3 genomes

AF:

0.430

AC:

65269

AN:

151884

Hom.:

14930

Cov.:

show subpopulations

Gnomad AFR

AF:

0.276

Gnomad AMI

AF:

0.577

Gnomad AMR

AF:

0.528

Gnomad ASJ

AF:

0.619

Gnomad EAS

AF:

0.380

Gnomad SAS

AF:

0.522

Gnomad FIN

AF:

0.421

Gnomad MID

AF:

0.434

Gnomad NFE

AF:

0.487

Gnomad OTH

AF:

0.464

GnomAD3 exomes

AF:

0.489

AC:

121672

AN:

248828

Hom.:

31316

AF XY:

0.492

AC XY:

66227

AN XY:

134672

show subpopulations

Gnomad AFR exome

AF:

0.270

Gnomad AMR exome

AF:

0.656

Gnomad ASJ exome

AF:

0.609

Gnomad EAS exome

AF:

0.363

Gnomad SAS exome

AF:

0.534

Gnomad FIN exome

AF:

0.408

Gnomad NFE exome

AF:

0.482

Gnomad OTH exome

AF:

0.492

GnomAD4 exome

AF:

0.480

AC:

676870

AN:

1410986

Hom.:

166960

Cov.:

AF XY:

0.483

AC XY:

339973

AN XY:

704054

show subpopulations

Gnomad4 AFR exome

AF:

0.261

Gnomad4 AMR exome

AF:

0.640

Gnomad4 ASJ exome

AF:

0.606

Gnomad4 EAS exome

AF:

0.401

Gnomad4 SAS exome

AF:

0.537

Gnomad4 FIN exome

AF:

0.410

Gnomad4 NFE exome

AF:

0.479

Gnomad4 OTH exome

AF:

0.473

GnomAD4 genome

AF:

0.430

AC:

65324

AN:

152000

Hom.:

14946

Cov.:

AF XY:

0.430

AC XY:

31976

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.276

Gnomad4 AMR

AF:

0.528

Gnomad4 ASJ

AF:

0.619

Gnomad4 EAS

AF:

0.380

Gnomad4 SAS

AF:

0.524

Gnomad4 FIN

AF:

0.421

Gnomad4 NFE

AF:

0.487

Gnomad4 OTH

AF:

0.461

Alfa

AF:

0.491

Hom.:

45900

Bravo

AF:

0.434

TwinsUK

AF:

0.482

AC:

1786

ALSPAC

AF:

0.490

AC:

1887

ESP6500AA

AF:

0.285

AC:

1253

ESP6500EA

AF:

0.492

AC:

4229

ExAC

AF:

0.479

AC:

58171

Asia WGS

AF:

0.419

AC:

1458

AN:

3478

EpiCase

AF:

0.501

EpiControl

AF:

0.505

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 48% of total chromosomes in ExAC -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 06, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:4

Jun 25, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23385296) -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 22, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Farber lipogranulomatosis

Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.83

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.0010

DANN

Benign

0.30

DEOGEN2

Benign

0.24

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

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.62

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

MetaRNN

Benign

0.0000039

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.015

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

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.23

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

REVEL

Benign

0.046

Sift

Benign

0.66

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

Sift4G

Benign

0.95

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

Polyphen

0.0

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

Vest4

0.015, 0.0090, 0.018

MPC

0.0035

ClinPred

0.022

GERP RS

-11

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.016

gMVP

0.72

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