8-18073263-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The ENST00000314146.10(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. 14/17 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
ENST00000314146.10 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.03

Publications

29 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 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

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 VariationId is 402397.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.126-1873G>A		intron_variant	Intron 2 of 13	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.126-1873G>A		intron_variant	Intron 2 of 13	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

GnomAD2 exomes

AF:

0.470

AC:

108245

AN:

230130

AF XY:

0.472

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.250

AC:

7941

AN:

31784

American (AMR)

AF:

0.623

AC:

24737

AN:

39676

Ashkenazi Jewish (ASJ)

AF:

0.597

AC:

14543

AN:

24376

East Asian (EAS)

AF:

0.381

AC:

14388

AN:

37722

South Asian (SAS)

AF:

0.517

AC:

41929

AN:

81040

European-Finnish (FIN)

AF:

0.400

AC:

20232

AN:

50576

Middle Eastern (MID)

AF:

0.473

AC:

2584

AN:

5462

European-Non Finnish (NFE)

AF:

0.468

AC:

477808

AN:

1020694

Other (OTH)

AF:

0.458

AC:

25574

AN:

55800

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.352

Heterozygous variant carriers

14413

28827

43240

57654

72067

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13786

27572

41358

55144

68930

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.428

AC:

65129

AN:

152028

Hom.:

14867

Cov.:

AF XY:

0.429

AC XY:

31871

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.276

AC:

11439

AN:

41432

American (AMR)

AF:

0.528

AC:

8068

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.615

AC:

2135

AN:

3472

East Asian (EAS)

AF:

0.368

AC:

1906

AN:

5174

South Asian (SAS)

AF:

0.512

AC:

2466

AN:

4818

European-Finnish (FIN)

AF:

0.420

AC:

4426

AN:

10536

Middle Eastern (MID)

AF:

0.425

AC:

125

AN:

294

European-Non Finnish (NFE)

AF:

0.486

AC:

33024

AN:

67992

Other (OTH)

AF:

0.458

AC:

967

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1875

3750

5626

7501

9376

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

608

1216

1824

2432

3040

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.475

Hom.:

46486

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

Mar 28, 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: 47% of total chromosomes in ExAC -

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

- -

not provided

Benign:2

Jun 19, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

- -

Farber lipogranulomatosis

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

0.11

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.69

CADD

Benign

1.1

(source)

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

PhyloP100

-1.0

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

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over