8-18075637-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.79-50G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0886 in 1,557,112 control chromosomes in the GnomAD database, including 6,974 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 881 hom., cov: 32)

Exomes 𝑓: 0.087 ( 6093 hom. )

Consequence

ASAH1
NM_177924.5 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -5.77

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=-0.92).

BP6

Variant 8-18075637-C-T is Benign according to our data. Variant chr8-18075637-C-T is described in ClinVar as Benign. ClinVar VariationId is 259276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASAH1	NM_177924.5 link	c.79-50G>A		intron_variant	Intron 1 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.79-50G>A		intron_variant	Intron 1 of 13	1	NM_177924.5	ENSP00000490272.1

Frequencies

GnomAD3 genomes

AF:

0.102

AC:

15573

AN:

152038

Hom.:

881

Cov.:

show subpopulations

Gnomad AFR

AF:

0.126

Gnomad AMI

AF:

0.123

Gnomad AMR

AF:

0.126

Gnomad ASJ

AF:

0.168

Gnomad EAS

AF:

0.0557

Gnomad SAS

AF:

0.119

Gnomad FIN

AF:

0.0962

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0830

Gnomad OTH

AF:

0.0926

GnomAD2 exomes

AF:

0.106

AC:

26586

AN:

250192

AF XY:

0.107

show subpopulations

Gnomad AFR exome

AF:

0.128

Gnomad AMR exome

AF:

0.162

Gnomad ASJ exome

AF:

0.173

Gnomad EAS exome

AF:

0.0572

Gnomad FIN exome

AF:

0.0941

Gnomad NFE exome

AF:

0.0837

Gnomad OTH exome

AF:

0.107

GnomAD4 exome

AF:

0.0871

AC:

122406

AN:

1404956

Hom.:

6093

Cov.:

AF XY:

0.0889

AC XY:

62459

AN XY:

702638

show subpopulations

African (AFR)

AF:

0.127

AC:

4100

AN:

32274

American (AMR)

AF:

0.159

AC:

7062

AN:

44544

Ashkenazi Jewish (ASJ)

AF:

0.168

AC:

4334

AN:

25760

East Asian (EAS)

AF:

0.0534

AC:

2103

AN:

39384

South Asian (SAS)

AF:

0.133

AC:

11329

AN:

84944

European-Finnish (FIN)

AF:

0.0915

AC:

4873

AN:

53228

Middle Eastern (MID)

AF:

0.120

AC:

676

AN:

5622

European-Non Finnish (NFE)

AF:

0.0778

AC:

82552

AN:

1060730

Other (OTH)

AF:

0.0920

AC:

5377

AN:

58470

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

4718

9437

14155

18874

23592

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3100

6200

9300

12400

15500

<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:

0.102

AC:

15589

AN:

152156

Hom.:

881

Cov.:

AF XY:

0.103

AC XY:

7688

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.126

AC:

5242

AN:

41492

American (AMR)

AF:

0.125

AC:

1919

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.168

AC:

582

AN:

3472

East Asian (EAS)

AF:

0.0554

AC:

287

AN:

5176

South Asian (SAS)

AF:

0.119

AC:

575

AN:

4820

European-Finnish (FIN)

AF:

0.0962

AC:

1018

AN:

10578

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0830

AC:

5644

AN:

68008

Other (OTH)

AF:

0.0921

AC:

194

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

715

1430

2144

2859

3574

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

170

340

510

680

850

<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:

0.0771

Hom.:

240

Bravo

AF:

0.106

Asia WGS

AF:

0.0660

AC:

232

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 28, 2018

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

-0.92

CADD

Benign

0.0040

(source)

DANN

Benign

0.77

PhyloP100

-5.8

PromoterAI

0.020

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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