Genetic Variant NM_177924.5:c.125+1346G>A (chr8-18074195-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.125+1346G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.697 in 152,064 control chromosomes in the GnomAD database, including 41,420 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 0.70 ( 41420 hom., cov: 32)

Consequence

ASAH1
NM_177924.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.420

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:

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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=-0.79).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.892 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASAH1	NM_177924.5 link	c.125+1346G>A		intron_variant	Intron 2 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.125+1346G>A		intron_variant	Intron 2 of 13	1	NM_177924.5	ENSP00000490272.1		Q13510-1

Frequencies

GnomAD3 genomes

AF:

0.697

AC:

105949

AN:

151946

Hom.:

41412

Cov.:

show subpopulations

Gnomad AFR

AF:

0.338

Gnomad AMI

AF:

0.876

Gnomad AMR

AF:

0.691

Gnomad ASJ

AF:

0.797

Gnomad EAS

AF:

0.509

Gnomad SAS

AF:

0.669

Gnomad FIN

AF:

0.863

Gnomad MID

AF:

0.826

Gnomad NFE

AF:

0.898

Gnomad OTH

AF:

0.739

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.697

AC:

105978

AN:

152064

Hom.:

41420

Cov.:

AF XY:

0.692

AC XY:

51415

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.337

AC:

13970

AN:

41430

American (AMR)

AF:

0.692

AC:

10557

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.797

AC:

2763

AN:

3468

East Asian (EAS)

AF:

0.510

AC:

2624

AN:

5148

South Asian (SAS)

AF:

0.668

AC:

3225

AN:

4826

European-Finnish (FIN)

AF:

0.863

AC:

9146

AN:

10604

Middle Eastern (MID)

AF:

0.830

AC:

244

AN:

294

European-Non Finnish (NFE)

AF:

0.898

AC:

61080

AN:

68002

Other (OTH)

AF:

0.742

AC:

1570

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1178

2357

3535

4714

5892

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

786

1572

2358

3144

3930

<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:

0.611

Hom.:

7773

Bravo

AF:

0.671

Asia WGS

AF:

0.601

AC:

2089

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

6.3

(source)

DANN

Benign

0.58

PhyloP100

0.42

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over