chr8-18067230-A-T

Position:

chr8-18067230-A-T

Variant summary

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

The ENST00000637790.2(ASAH1):c.372T>A(p.Asp124Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0407 in 1,605,582 control chromosomes in the GnomAD database, including 1,602 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D124A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.034 ( 118 hom., cov: 31)

Exomes 𝑓: 0.041 ( 1484 hom. )

Consequence

ASAH1
ENST00000637790.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.24

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=0.0013536811).

BP6

Variant 8-18067230-A-T is Benign according to our data. Variant chr8-18067230-A-T is described in ClinVar as [Benign]. Clinvar id is 362381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-18067230-A-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0513 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.372T>A	p.Asp124Glu	missense_variant	5/14	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.372T>A	p.Asp124Glu	missense_variant	5/14	1	NM_177924.5	ENSP00000490272	P2	Q13510-1

Frequencies

GnomAD3 genomes

AF:

0.0337

AC:

5016

AN:

148786

Hom.:

118

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0109

Gnomad AMI

AF:

0.117

Gnomad AMR

AF:

0.0250

Gnomad ASJ

AF:

0.0705

Gnomad EAS

AF:

0.000777

Gnomad SAS

AF:

0.0572

Gnomad FIN

AF:

0.0500

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0452

Gnomad OTH

AF:

0.0320

GnomAD3 exomes

AF:

0.0388

AC:

9709

AN:

249922

Hom.:

260

AF XY:

0.0421

AC XY:

5693

AN XY:

135202

show subpopulations

Gnomad AFR exome

AF:

0.0108

Gnomad AMR exome

AF:

0.0162

Gnomad ASJ exome

AF:

0.0683

Gnomad EAS exome

AF:

0.000708

Gnomad SAS exome

AF:

0.0656

Gnomad FIN exome

AF:

0.0472

Gnomad NFE exome

AF:

0.0442

Gnomad OTH exome

AF:

0.0448

GnomAD4 exome

AF:

0.0414

AC:

60273

AN:

1456692

Hom.:

1484

Cov.:

AF XY:

0.0424

AC XY:

30728

AN XY:

724554

show subpopulations

Gnomad4 AFR exome

AF:

0.0106

Gnomad4 AMR exome

AF:

0.0185

Gnomad4 ASJ exome

AF:

0.0671

Gnomad4 EAS exome

AF:

0.000303

Gnomad4 SAS exome

AF:

0.0646

Gnomad4 FIN exome

AF:

0.0468

Gnomad4 NFE exome

AF:

0.0421

Gnomad4 OTH exome

AF:

0.0406

GnomAD4 genome

AF:

0.0337

AC:

5015

AN:

148890

Hom.:

118

Cov.:

AF XY:

0.0343

AC XY:

2489

AN XY:

72652

show subpopulations

Gnomad4 AFR

AF:

0.0109

Gnomad4 AMR

AF:

0.0249

Gnomad4 ASJ

AF:

0.0705

Gnomad4 EAS

AF:

0.000779

Gnomad4 SAS

AF:

0.0569

Gnomad4 FIN

AF:

0.0500

Gnomad4 NFE

AF:

0.0452

Gnomad4 OTH

AF:

0.0322

Alfa

AF:

0.0410

Hom.:

Bravo

AF:

0.0297

TwinsUK

AF:

0.0410

AC:

152

ALSPAC

AF:

0.0413

AC:

159

ESP6500AA

AF:

0.0136

AC:

ESP6500EA

AF:

0.0450

AC:

387

ExAC

AF:

0.0414

AC:

5022

Asia WGS

AF:

0.0250

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2018	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 16, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 17, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Farber lipogranulomatosis

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.68

CADD

Benign

9.7

DANN

Benign

0.97

DEOGEN2

Benign

0.31

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

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.77

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

MetaRNN

Benign

0.0014

T;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

-1.1

MutationAssessor

Benign

-0.29

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

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Benign

0.23

PROVEAN

Benign

-1.1

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

REVEL

Benign

0.064

Sift

Benign

0.12

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

Sift4G

Benign

0.095

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

Polyphen

0.0

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

Vest4

0.069, 0.017, 0.068

MutPred

0.15

Gain of solvent accessibility (P = 0.2601);Gain of solvent accessibility (P = 0.2601);Gain of solvent accessibility (P = 0.2601);.;.;.;Gain of solvent accessibility (P = 0.2601);.;Gain of solvent accessibility (P = 0.2601);Gain of solvent accessibility (P = 0.2601);.;Gain of solvent accessibility (P = 0.2601);.;.;.;Gain of solvent accessibility (P = 0.2601);.;.;.;Gain of solvent accessibility (P = 0.2601);Gain of solvent accessibility (P = 0.2601);.;.;.;.;

MPC

0.0033

ClinPred

0.0035

GERP RS

-2.9

Varity_R

0.12

gMVP

0.77

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