rs1071645

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_177924.5(ASAH1):c.214G>A(p.Val72Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.478 in 1,553,802 control chromosomes in the GnomAD database, including 182,271 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: 𝑓 0.43 ( 14935 hom., cov: 31)

Exomes 𝑓: 0.48 ( 167336 hom. )

Consequence

ASAH1
NM_177924.5 missense, splice_region

Scores

Splicing: ADA: 0.00001074

Clinical Significance

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

Conservation

PhyloP100: 0.552

Publications

41 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.661483E-6).

BP6

Variant 8-18071302-C-T is Benign according to our data. Variant chr8-18071302-C-T is described in ClinVar as Benign. ClinVar VariationId is 259278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.519 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASAH1	NM_177924.5 link	c.214G>A	p.Val72Met	missense_variant, splice_region_variant	Exon 3 of 14	ENST00000637790.2	NP_808592.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASAH1	ENST00000637790.2 link	c.214G>A	p.Val72Met	missense_variant, splice_region_variant	Exon 3 of 14	1	NM_177924.5	ENSP00000490272.1

Frequencies

GnomAD3 genomes

AF:

0.430

AC:

65204

AN:

151720

Hom.:

14920

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:

0.381

Gnomad SAS

AF:

0.523

Gnomad FIN

AF:

0.420

Gnomad MID

AF:

0.430

Gnomad NFE

AF:

0.487

Gnomad OTH

AF:

0.465

GnomAD2 exomes

AF:

0.487

AC:

112543

AN:

230982

AF XY:

0.490

show subpopulations

Gnomad AFR exome

AF:

0.267

Gnomad AMR exome

AF:

0.653

Gnomad ASJ exome

AF:

0.608

Gnomad EAS exome

AF:

0.361

Gnomad FIN exome

AF:

0.409

Gnomad NFE exome

AF:

0.480

Gnomad OTH exome

AF:

0.494

GnomAD4 exome

AF:

0.484

AC:

678020

AN:

1401964

Hom.:

167336

Cov.:

AF XY:

0.486

AC XY:

339797

AN XY:

698614

show subpopulations

African (AFR)

AF:

0.265

AC:

8608

AN:

32480

American (AMR)

AF:

0.638

AC:

27572

AN:

43216

Ashkenazi Jewish (ASJ)

AF:

0.609

AC:

15478

AN:

25430

East Asian (EAS)

AF:

0.401

AC:

15721

AN:

39158

South Asian (SAS)

AF:

0.537

AC:

44660

AN:

83134

European-Finnish (FIN)

AF:

0.411

AC:

21385

AN:

51992

Middle Eastern (MID)

AF:

0.486

AC:

2545

AN:

5242

European-Non Finnish (NFE)

AF:

0.484

AC:

514326

AN:

1063098

Other (OTH)

AF:

0.476

AC:

27725

AN:

58214

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

14712

29425

44137

58850

73562

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15016

30032

45048

60064

75080

<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:

0.430

AC:

65259

AN:

151838

Hom.:

14935

Cov.:

AF XY:

0.431

AC XY:

31928

AN XY:

74156

show subpopulations

African (AFR)

AF:

0.276

AC:

11435

AN:

41406

American (AMR)

AF:

0.529

AC:

8067

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.619

AC:

2144

AN:

3464

East Asian (EAS)

AF:

0.381

AC:

1965

AN:

5152

South Asian (SAS)

AF:

0.524

AC:

2527

AN:

4820

European-Finnish (FIN)

AF:

0.420

AC:

4406

AN:

10486

Middle Eastern (MID)

AF:

0.429

AC:

126

AN:

294

European-Non Finnish (NFE)

AF:

0.487

AC:

33089

AN:

67932

Other (OTH)

AF:

0.461

AC:

974

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1798

3596

5395

7193

8991

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

610

1220

1830

2440

3050

<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:

0.472

Hom.:

34114

Bravo

AF:

0.434

TwinsUK

AF:

0.483

AC:

1791

ALSPAC

AF:

0.489

AC:

1883

ESP6500AA

AF:

0.289

AC:

1275

ESP6500EA

AF:

0.493

AC:

4243

ExAC

AF:

0.463

AC:

56120

Asia WGS

AF:

0.419

AC:

1455

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

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

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 20, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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: 27026573) -

not specified

Benign:4

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: 54% of total chromosomes in ExAC -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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 12, 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

0.064

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.26

(source)

DANN

Benign

0.32

DEOGEN2

Benign

0.22

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

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.093

LIST_S2

Benign

0.044

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

MetaRNN

Benign

0.000043

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;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.41

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

PhyloP100

0.55

PrimateAI

Benign

0.26

PROVEAN

Benign

0.28

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

REVEL

Benign

0.038

Sift

Benign

0.21

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

Sift4G

Benign

0.10

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

Polyphen

0.0010

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

Vest4

0.055, 0.032, 0.043, 0.068

MPC

0.0031

ClinPred

0.0036

GERP RS

-3.3

Varity_R

0.016

gMVP

0.67

Mutation Taster

=89/11

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000011

dbscSNV1_RF

Benign

0.050

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