8-18064412-T-C

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.457+45A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.617 in 1,336,928 control chromosomes in the GnomAD database, including 259,612 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.63 ( 30581 hom., cov: 32)

Exomes 𝑓: 0.61 ( 229031 hom. )

Consequence

ASAH1
NM_177924.5 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.14

Publications

10 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=3.4235284E-6).

BP6

Variant 8-18064412-T-C is Benign according to our data. Variant chr8-18064412-T-C is described in ClinVar as Benign. ClinVar VariationId is 259281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.672 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASAH1	NM_177924.5 link	c.457+45A>G		intron_variant	Intron 6 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.457+45A>G		intron_variant	Intron 6 of 13	1	NM_177924.5	ENSP00000490272.1

Frequencies

GnomAD3 genomes

AF:

0.631

AC:

95896

AN:

151900

Hom.:

30564

Cov.:

show subpopulations

Gnomad AFR

AF:

0.679

Gnomad AMI

AF:

0.597

Gnomad AMR

AF:

0.550

Gnomad ASJ

AF:

0.501

Gnomad EAS

AF:

0.504

Gnomad SAS

AF:

0.470

Gnomad FIN

AF:

0.663

Gnomad MID

AF:

0.652

Gnomad NFE

AF:

0.644

Gnomad OTH

AF:

0.631

GnomAD2 exomes

AF:

0.577

AC:

125685

AN:

217760

AF XY:

0.576

show subpopulations

Gnomad AFR exome

AF:

0.679

Gnomad AMR exome

AF:

0.399

Gnomad ASJ exome

AF:

0.514

Gnomad EAS exome

AF:

0.511

Gnomad FIN exome

AF:

0.683

Gnomad NFE exome

AF:

0.652

Gnomad OTH exome

AF:

0.594

GnomAD4 exome

AF:

0.615

AC:

728388

AN:

1184910

Hom.:

229031

Cov.:

AF XY:

0.609

AC XY:

365669

AN XY:

600402

show subpopulations

African (AFR)

AF:

0.680

AC:

18404

AN:

27058

American (AMR)

AF:

0.418

AC:

17707

AN:

42410

Ashkenazi Jewish (ASJ)

AF:

0.514

AC:

12383

AN:

24114

East Asian (EAS)

AF:

0.500

AC:

18535

AN:

37042

South Asian (SAS)

AF:

0.454

AC:

35509

AN:

78240

European-Finnish (FIN)

AF:

0.680

AC:

35152

AN:

51674

Middle Eastern (MID)

AF:

0.603

AC:

3170

AN:

5256

European-Non Finnish (NFE)

AF:

0.641

AC:

556768

AN:

868130

Other (OTH)

AF:

0.603

AC:

30760

AN:

50986

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

14408

28816

43223

57631

72039

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13072

26144

39216

52288

65360

<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:

0.631

AC:

95960

AN:

152018

Hom.:

30581

Cov.:

AF XY:

0.626

AC XY:

46471

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.679

AC:

28135

AN:

41464

American (AMR)

AF:

0.550

AC:

8405

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.501

AC:

1734

AN:

3462

East Asian (EAS)

AF:

0.504

AC:

2608

AN:

5172

South Asian (SAS)

AF:

0.469

AC:

2257

AN:

4812

European-Finnish (FIN)

AF:

0.663

AC:

6994

AN:

10554

Middle Eastern (MID)

AF:

0.663

AC:

195

AN:

294

European-Non Finnish (NFE)

AF:

0.644

AC:

43753

AN:

67958

Other (OTH)

AF:

0.633

AC:

1337

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1825

3650

5475

7300

9125

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

782

1564

2346

3128

3910

<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:

0.631

Hom.:

84063

Bravo

AF:

0.622

TwinsUK

AF:

0.653

AC:

2421

ALSPAC

AF:

0.641

AC:

2469

ESP6500AA

AF:

0.672

AC:

2955

ESP6500EA

AF:

0.642

AC:

5513

ExAC

AF:

0.572

AC:

68618

Asia WGS

AF:

0.532

AC:

1852

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

- -

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

AlphaMissense

Benign

0.085

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.021

(source)

DANN

Benign

0.52

DEOGEN2

Benign

0.0060

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.29

MetaRNN

Benign

0.0000034

PhyloP100

-1.1

GERP RS

-0.49

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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