8-18056461-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_177924.5(ASAH1):c.*1073C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.762 in 152,126 control chromosomes in the GnomAD database, including 44,952 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.76 (44951 hom., cov: 32)
  • Exomes 𝑓: 0.50 (1 hom.)
• Consequence: ASAH1 NM_177924.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.72

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 8-18056461-G-A is Benign according to our data. Variant chr8-18056461-G-A is described in ClinVar as [Benign]. Clinvar id is 362350.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.91 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASAH1	NM_177924.5	c.*1073C>T		3_prime_UTR_variant	14/14	ENST00000637790.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASAH1	ENST00000637790.2	c.*1073C>T		3_prime_UTR_variant	14/14	1	NM_177924.5	P2

Frequencies

GnomAD3 genomes AF: 0.762 AC: 115859 AN: 152004 Hom.: 44914 Cov.: 32

Gnomad AFR AF: 0.918

Gnomad AMI AF: 0.734

Gnomad AMR AF: 0.680

Gnomad ASJ AF: 0.697

Gnomad EAS AF: 0.560

Gnomad SAS AF: 0.663

Gnomad FIN AF: 0.708

Gnomad MID AF: 0.744

Gnomad NFE AF: 0.721

Gnomad OTH AF: 0.741

GnomAD4 exome AF: 0.500 AC: 2 AN: 4 Hom.: 1 Cov.: 0 AF XY: 0.500 AC XY: 2 AN XY: 4

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 1.00

GnomAD4 genome AF: 0.762 AC: 115945 AN: 152122 Hom.: 44951 Cov.: 32 AF XY: 0.756 AC XY: 56237 AN XY: 74366

Gnomad4 AFR AF: 0.918

Gnomad4 AMR AF: 0.679

Gnomad4 ASJ AF: 0.697

Gnomad4 EAS AF: 0.560

Gnomad4 SAS AF: 0.662

Gnomad4 FIN AF: 0.708

Gnomad4 NFE AF: 0.721

Gnomad4 OTH AF: 0.741

Alfa AF: 0.723 Hom.: 80410

Bravo AF: 0.763

Asia WGS AF: 0.638 AC: 2222 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Farber lipogranulomatosis Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
Cadd	Benign	0.011
Dann	Benign	0.44

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

LitVar

Other links and lift over

dbSNP: rs7508; hg19: chr8-17913970;