Genetic Variant ASAH1:c.304-344G>A (chr8-18067642-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_177924.5(ASAH1):c.304-344G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 157,942 control chromosomes in the GnomAD database, including 14,996 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.42 ( 14396 hom., cov: 30)

Exomes 𝑓: 0.42 ( 600 hom. )

Consequence

ASAH1
NM_177924.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.313

Publications

12 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.515 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASAH1	NM_177924.5 link	c.304-344G>A		intron_variant	Intron 4 of 13	ENST00000637790.2	NP_808592.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASAH1	ENST00000637790.2 link	c.304-344G>A		intron_variant	Intron 4 of 13	1	NM_177924.5	ENSP00000490272.1

Frequencies

GnomAD3 genomes

AF:

0.421

AC:

63714

AN:

151370

Hom.:

14379

Cov.:

show subpopulations

Gnomad AFR

AF:

0.254

Gnomad AMI

AF:

0.572

Gnomad AMR

AF:

0.524

Gnomad ASJ

AF:

0.618

Gnomad EAS

AF:

0.375

Gnomad SAS

AF:

0.516

Gnomad FIN

AF:

0.413

Gnomad MID

AF:

0.423

Gnomad NFE

AF:

0.484

Gnomad OTH

AF:

0.456

GnomAD4 exome

AF:

0.421

AC:

2716

AN:

6450

Hom.:

600

Cov.:

AF XY:

0.427

AC XY:

2058

AN XY:

4822

show subpopulations

African (AFR)

AF:

0.202

AC:

AN:

124

American (AMR)

AF:

0.523

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.531

AC:

AN:

East Asian (EAS)

AF:

0.399

AC:

114

AN:

286

South Asian (SAS)

AF:

0.543

AC:

AN:

162

European-Finnish (FIN)

AF:

0.310

AC:

AN:

Middle Eastern (MID)

AF:

0.357

AC:

AN:

European-Non Finnish (NFE)

AF:

0.424

AC:

2314

AN:

5452

Other (OTH)

AF:

0.393

AC:

AN:

196

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

119

178

238

297

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.421

AC:

63772

AN:

151492

Hom.:

14396

Cov.:

AF XY:

0.421

AC XY:

31161

AN XY:

74006

show subpopulations

African (AFR)

AF:

0.254

AC:

10499

AN:

41372

American (AMR)

AF:

0.525

AC:

7987

AN:

15216

Ashkenazi Jewish (ASJ)

AF:

0.618

AC:

2135

AN:

3452

East Asian (EAS)

AF:

0.375

AC:

1922

AN:

5124

South Asian (SAS)

AF:

0.518

AC:

2494

AN:

4814

European-Finnish (FIN)

AF:

0.413

AC:

4337

AN:

10492

Middle Eastern (MID)

AF:

0.429

AC:

126

AN:

294

European-Non Finnish (NFE)

AF:

0.484

AC:

32803

AN:

67722

Other (OTH)

AF:

0.453

AC:

950

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1797

3595

5392

7190

8987

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

598

1196

1794

2392

2990

<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:

0.483

Hom.:

17010

Bravo

AF:

0.426

Asia WGS

AF:

0.410

AC:

1424

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

6.7

(source)

DANN

Benign

0.82

PhyloP100

0.31

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

Computational scores

Splicing

Publications

Other links and lift over