8-18073263-C-T

Position:

chr8-18073263-C-T

Variant summary

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

The NM_001127505.3(ASAH1):c.187G>A(p.Val63Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.464 in 1,499,158 control chromosomes in the GnomAD database, including 172,931 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.43 ( 14867 hom., cov: 32)

Exomes 𝑓: 0.47 ( 158064 hom. )

Consequence

ASAH1
NM_001127505.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.03

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:

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=3.0002971E-5).

BP6

Variant 8-18073263-C-T is Benign according to our data. Variant chr8-18073263-C-T is described in ClinVar as [Benign]. Clinvar id is 402397.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-18073263-C-T 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/exons	MANE	Protein	UniProt
ASAH1	NM_177924.5 linkuse as main transcript	c.126-1873G>A		intron_variant		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.126-1873G>A		intron_variant		1	NM_177924.5	ENSP00000490272.1		Q13510-1

Frequencies

GnomAD3 genomes

AF:

0.428

AC:

65074

AN:

151910

Hom.:

14851

Cov.:

show subpopulations

Gnomad AFR

AF:

0.276

Gnomad AMI

AF:

0.628

Gnomad AMR

AF:

0.527

Gnomad ASJ

AF:

0.615

Gnomad EAS

AF:

0.368

Gnomad SAS

AF:

0.510

Gnomad FIN

AF:

0.420

Gnomad MID

AF:

0.427

Gnomad NFE

AF:

0.486

Gnomad OTH

AF:

0.461

GnomAD3 exomes

AF:

0.470

AC:

108245

AN:

230130

Hom.:

27157

AF XY:

0.472

AC XY:

58965

AN XY:

124946

show subpopulations

Gnomad AFR exome

AF:

0.254

Gnomad AMR exome

AF:

0.639

Gnomad ASJ exome

AF:

0.602

Gnomad EAS exome

AF:

0.337

Gnomad SAS exome

AF:

0.503

Gnomad FIN exome

AF:

0.405

Gnomad NFE exome

AF:

0.465

Gnomad OTH exome

AF:

0.477

GnomAD4 exome

AF:

0.467

AC:

629736

AN:

1347130

Hom.:

158064

Cov.:

AF XY:

0.470

AC XY:

315199

AN XY:

670602

show subpopulations

Gnomad4 AFR exome

AF:

0.250

Gnomad4 AMR exome

AF:

0.623

Gnomad4 ASJ exome

AF:

0.597

Gnomad4 EAS exome

AF:

0.381

Gnomad4 SAS exome

AF:

0.517

Gnomad4 FIN exome

AF:

0.400

Gnomad4 NFE exome

AF:

0.468

Gnomad4 OTH exome

AF:

0.458

GnomAD4 genome

AF:

0.428

AC:

65129

AN:

152028

Hom.:

14867

Cov.:

AF XY:

0.429

AC XY:

31871

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.276

Gnomad4 AMR

AF:

0.528

Gnomad4 ASJ

AF:

0.615

Gnomad4 EAS

AF:

0.368

Gnomad4 SAS

AF:

0.512

Gnomad4 FIN

AF:

0.420

Gnomad4 NFE

AF:

0.486

Gnomad4 OTH

AF:

0.458

Alfa

AF:

0.488

Hom.:

32369

Bravo

AF:

0.433

TwinsUK

AF:

0.480

AC:

1781

ALSPAC

AF:

0.488

AC:

1880

ESP6500AA

AF:

0.281

AC:

880

ESP6500EA

AF:

0.487

AC:

3484

ExAC

AF:

0.464

AC:

55816

Asia WGS

AF:

0.404

AC:

1405

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 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: 47% of total chromosomes in ExAC -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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. -

Spinal muscular atrophy-progressive myoclonic epilepsy syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Farber lipogranulomatosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.69

CADD

Benign

1.1

DANN

Benign

0.30

DEOGEN2

Benign

0.0028

.;T

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0087

LIST_S2

Benign

0.23

T;T

MetaRNN

Benign

0.000030

T;T

MetaSVM

Benign

-0.93

PROVEAN

Benign

-0.060

N;.

REVEL

Benign

0.043

Sift

Benign

0.29

T;.

Sift4G

Benign

0.38

T;.

Vest4

0.024

ClinPred

0.0022

GERP RS

-1.6

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