8-18084277-T-A

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP3BS1_Supporting

The NM_004315.6(ASAH1):c.126+399A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,440,648 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 1 hom. )

Consequence

ASAH1
NM_004315.6 intron

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.0780

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 links:

ASAH1-AS1 (HGNC:55603): (ASAH1 antisense RNA 1)

ASAH1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000112 (144/1288334) while in subpopulation MID AF= 0.00221 (8/3614). AF 95% confidence interval is 0.0011. There are 1 homozygotes in gnomad4_exome. There are 65 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ASAH1	NM_004315.6 link	c.126+399A>T	intron_variant	Intron 1 of 13		NP_004306.3	Q13510-2Q53H01A8K0B6
ASAH1	NM_001127505.3 link	c.126+399A>T	intron_variant	Intron 1 of 13		NP_001120977.1	Q13510-3Q53H01A8K0B6
ASAH1	NM_177924.5 link	c.-219A>T	upstream_gene_variant		ENST00000637790.2	NP_808592.2	Q13510-1Q53H01A8K0B6
ASAH1	XM_005273504.4 link	c.-349A>T	upstream_gene_variant			XP_005273561.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASAH1	ENST00000637790.2 link	c.-219A>T		upstream_gene_variant		1	NM_177924.5	ENSP00000490272.1		Q13510-1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.000478

GnomAD4 exome

AF:

0.000112

AC:

144

AN:

1288334

Hom.:

Cov.:

AF XY:

0.000104

AC XY:

AN XY:

626388

show subpopulations

Gnomad4 AFR exome

AF:

0.000247

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00264

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000317

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000589

Gnomad4 OTH exome

AF:

0.000299

GnomAD4 genome

AF:

0.000112

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.000473

Bravo

AF:

0.000128

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Farber lipogranulomatosis;C1834569:Spinal muscular atrophy-progressive myoclonic epilepsy syndrome

Uncertain:1

Jan 10, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Farber lipogranulomatosis

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

5.0

DANN

Benign

0.85

FATHMM_MKL

Benign

0.12

GERP RS

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.54

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.54

Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over