NM_177924.5:c.79-3C>T

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.79-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0901 in 1,612,940 control chromosomes in the GnomAD database, including 7,508 homozygotes. In-silico tool predicts 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 (★★).

Frequency

Genomes: 𝑓 0.11 ( 958 hom., cov: 32)

Exomes 𝑓: 0.088 ( 6550 hom. )

Consequence

ASAH1
NM_177924.5 splice_region, intron

Scores

Splicing: ADA: 0.0004532

Clinical Significance

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

Conservation

PhyloP100: 0.173

Publications

7 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 (BayesDel_noAF=-0.81).

BP6

Variant 8-18075590-G-A is Benign according to our data. Variant chr8-18075590-G-A is described in ClinVar as Benign. ClinVar VariationId is 259275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASAH1	NM_177924.5 link	c.79-3C>T		splice_region_variant, intron_variant	Intron 1 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.79-3C>T		splice_region_variant, intron_variant	Intron 1 of 13	1	NM_177924.5	ENSP00000490272.1		Q13510-1

Frequencies

GnomAD3 genomes

AF:

0.106

AC:

16178

AN:

152082

Hom.:

958

Cov.:

show subpopulations

Gnomad AFR

AF:

0.140

Gnomad AMI

AF:

0.123

Gnomad AMR

AF:

0.127

Gnomad ASJ

AF:

0.168

Gnomad EAS

AF:

0.0557

Gnomad SAS

AF:

0.119

Gnomad FIN

AF:

0.0954

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0830

Gnomad OTH

AF:

0.0945

GnomAD2 exomes

AF:

0.108

AC:

27036

AN:

251334

AF XY:

0.108

show subpopulations

Gnomad AFR exome

AF:

0.144

Gnomad AMR exome

AF:

0.162

Gnomad ASJ exome

AF:

0.174

Gnomad EAS exome

AF:

0.0573

Gnomad FIN exome

AF:

0.0944

Gnomad NFE exome

AF:

0.0840

Gnomad OTH exome

AF:

0.107

GnomAD4 exome

AF:

0.0885

AC:

129204

AN:

1460738

Hom.:

6550

Cov.:

AF XY:

0.0900

AC XY:

65437

AN XY:

726704

show subpopulations

African (AFR)

AF:

0.143

AC:

4779

AN:

33434

American (AMR)

AF:

0.159

AC:

7131

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.169

AC:

4405

AN:

26124

East Asian (EAS)

AF:

0.0535

AC:

2124

AN:

39680

South Asian (SAS)

AF:

0.134

AC:

11552

AN:

86208

European-Finnish (FIN)

AF:

0.0918

AC:

4901

AN:

53410

Middle Eastern (MID)

AF:

0.122

AC:

703

AN:

5762

European-Non Finnish (NFE)

AF:

0.0792

AC:

87948

AN:

1111044

Other (OTH)

AF:

0.0938

AC:

5661

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

5527

11053

16580

22106

27633

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3382

6764

10146

13528

16910

<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:

0.106

AC:

16197

AN:

152202

Hom.:

958

Cov.:

AF XY:

0.107

AC XY:

7983

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.141

AC:

5841

AN:

41534

American (AMR)

AF:

0.126

AC:

1932

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.168

AC:

582

AN:

3472

East Asian (EAS)

AF:

0.0554

AC:

287

AN:

5180

South Asian (SAS)

AF:

0.119

AC:

574

AN:

4822

European-Finnish (FIN)

AF:

0.0954

AC:

1009

AN:

10578

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0830

AC:

5646

AN:

68008

Other (OTH)

AF:

0.0940

AC:

198

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

734

1467

2201

2934

3668

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

174

348

522

696

870

<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:

0.101

Hom.:

440

Bravo

AF:

0.111

Asia WGS

AF:

0.0680

AC:

236

AN:

3478

EpiCase

AF:

0.0866

EpiControl

AF:

0.0899

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Oct 23, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 13, 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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Farber lipogranulomatosis

Benign:2

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. -

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

BayesDel_noAF

Benign

-0.81

CADD

Benign

6.6

(source)

DANN

Benign

0.60

PhyloP100

0.17

PromoterAI

-0.018

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00045

dbscSNV1_RF

Benign

0.020

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