8-18067340-C-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.304-42G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.345 in 1,179,346 control chromosomes in the GnomAD database, including 73,235 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.36 ( 9758 hom., cov: 31)

Exomes 𝑓: 0.34 ( 63477 hom. )

Consequence

ASAH1
NM_177924.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.54

Publications

4 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=-0.82).

BP6

Variant 8-18067340-C-T is Benign according to our data. Variant chr8-18067340-C-T is described in ClinVar as Benign. ClinVar VariationId is 259280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.504 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASAH1	NM_177924.5 link	c.304-42G>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.304-42G>A		intron_variant	Intron 4 of 13	1	NM_177924.5	ENSP00000490272.1

Frequencies

GnomAD3 genomes

AF:

0.358

AC:

53156

AN:

148660

Hom.:

9759

Cov.:

show subpopulations

Gnomad AFR

AF:

0.291

Gnomad AMI

AF:

0.407

Gnomad AMR

AF:

0.444

Gnomad ASJ

AF:

0.504

Gnomad EAS

AF:

0.381

Gnomad SAS

AF:

0.520

Gnomad FIN

AF:

0.305

Gnomad MID

AF:

0.336

Gnomad NFE

AF:

0.364

Gnomad OTH

AF:

0.360

GnomAD2 exomes

AF:

0.345

AC:

37816

AN:

109580

AF XY:

0.357

show subpopulations

Gnomad AFR exome

AF:

0.201

Gnomad AMR exome

AF:

0.448

Gnomad ASJ exome

AF:

0.451

Gnomad EAS exome

AF:

0.264

Gnomad FIN exome

AF:

0.285

Gnomad NFE exome

AF:

0.311

Gnomad OTH exome

AF:

0.324

GnomAD4 exome

AF:

0.343

AC:

353756

AN:

1030668

Hom.:

63477

Cov.:

AF XY:

0.347

AC XY:

178433

AN XY:

514074

show subpopulations

African (AFR)

AF:

0.250

AC:

5909

AN:

23626

American (AMR)

AF:

0.470

AC:

9953

AN:

21190

Ashkenazi Jewish (ASJ)

AF:

0.451

AC:

8541

AN:

18934

East Asian (EAS)

AF:

0.370

AC:

11185

AN:

30194

South Asian (SAS)

AF:

0.454

AC:

19486

AN:

42946

European-Finnish (FIN)

AF:

0.266

AC:

10920

AN:

41032

Middle Eastern (MID)

AF:

0.350

AC:

1336

AN:

3822

European-Non Finnish (NFE)

AF:

0.337

AC:

271251

AN:

805760

Other (OTH)

AF:

0.352

AC:

15175

AN:

43164

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

8803

17606

26408

35211

44014

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8898

17796

26694

35592

44490

<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:

0.358

AC:

53158

AN:

148678

Hom.:

9758

Cov.:

AF XY:

0.361

AC XY:

26178

AN XY:

72484

show subpopulations

African (AFR)

AF:

0.291

AC:

11905

AN:

40860

American (AMR)

AF:

0.444

AC:

6608

AN:

14868

Ashkenazi Jewish (ASJ)

AF:

0.504

AC:

1745

AN:

3464

East Asian (EAS)

AF:

0.381

AC:

1956

AN:

5136

South Asian (SAS)

AF:

0.521

AC:

2484

AN:

4770

European-Finnish (FIN)

AF:

0.305

AC:

2753

AN:

9018

Middle Eastern (MID)

AF:

0.324

AC:

AN:

278

European-Non Finnish (NFE)

AF:

0.364

AC:

24512

AN:

67322

Other (OTH)

AF:

0.358

AC:

735

AN:

2054

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1746

3493

5239

6986

8732

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

528

1056

1584

2112

2640

<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:

0.343

Hom.:

1880

Bravo

AF:

0.365

Asia WGS

AF:

0.397

AC:

1366

AN:

3438

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Aug 18, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

- -

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

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.24

(source)

DANN

Benign

0.16

PhyloP100

-1.5

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