rs35513736

chr8-18075590-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_177924.5(ASAH1):c.79-3C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0901 in 1,612,940 control chromosomes in the GnomAD database, including 7,508 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (958 hom., cov: 32)
  • Exomes 𝑓: 0.088 (6550 hom.)
• Consequence: ASAH1 NM_177924.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0004532
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.173

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 8-18075590-G-A is Benign according to our data. Variant chr8-18075590-G-A is described in ClinVar as [Benign]. Clinvar id is 259275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-18075590-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASAH1	NM_177924.5	c.79-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000637790.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASAH1	ENST00000637790.2	c.79-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_177924.5	P2

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16178 AN: 152082 Hom.: 958 Cov.: 32

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.0557

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.0954

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0830

Gnomad OTH AF: 0.0945

GnomAD3 exomes AF: 0.108 AC: 27036 AN: 251334 Hom.: 1686 AF XY: 0.108 AC XY: 14621 AN XY: 135844

Gnomad AFR exome AF: 0.144

Gnomad AMR exome AF: 0.162

Gnomad ASJ exome AF: 0.174

Gnomad EAS exome AF: 0.0573

Gnomad SAS exome AF: 0.132

Gnomad FIN exome AF: 0.0944

Gnomad NFE exome AF: 0.0840

Gnomad OTH exome AF: 0.107

GnomAD4 exome AF: 0.0885 AC: 129204 AN: 1460738 Hom.: 6550 Cov.: 31 AF XY: 0.0900 AC XY: 65437 AN XY: 726704

Gnomad4 AFR exome AF: 0.143

Gnomad4 AMR exome AF: 0.159

Gnomad4 ASJ exome AF: 0.169

Gnomad4 EAS exome AF: 0.0535

Gnomad4 SAS exome AF: 0.134

Gnomad4 FIN exome AF: 0.0918

Gnomad4 NFE exome AF: 0.0792

Gnomad4 OTH exome AF: 0.0938

GnomAD4 genome AF: 0.106 AC: 16197 AN: 152202 Hom.: 958 Cov.: 32 AF XY: 0.107 AC XY: 7983 AN XY: 74414

Gnomad4 AFR AF: 0.141

Gnomad4 AMR AF: 0.126

Gnomad4 ASJ AF: 0.168

Gnomad4 EAS AF: 0.0554

Gnomad4 SAS AF: 0.119

Gnomad4 FIN AF: 0.0954

Gnomad4 NFE AF: 0.0830

Gnomad4 OTH AF: 0.0940

Alfa AF: 0.0994 Hom.: 401

Bravo AF: 0.111

Asia WGS AF: 0.0680 AC: 236 AN: 3478

EpiCase AF: 0.0866

EpiControl AF: 0.0899

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Farber lipogranulomatosis Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Spinal muscular atrophy-progressive myoclonic epilepsy syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	6.6
Dann	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00045
dbscSNV1_RF	Benign	0.020
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

LitVar

Other links and lift over

dbSNP: rs35513736; hg19: chr8-17933099; COSMIC: COSV50502220; COSMIC: COSV50502220;