8-18057200-C-T

Position:

• chr8-18057200-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000314146.10(ASAH1):​c.*334G>A variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0224 in 303,576 control chromosomes in the GnomAD database, including 108 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (56 hom., cov: 32)
  • Exomes 𝑓: 0.020 (52 hom.)
• Consequence: ASAH1 ENST00000314146.10 splice_region
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.121

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 8-18057200-C-T is Benign according to our data. Variant chr8-18057200-C-T is described in ClinVar as [Benign]. Clinvar id is 362364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0253 (3853/152266) while in subpopulation AFR AF= 0.047 (1953/41544). AF 95% confidence interval is 0.0453. There are 56 homozygotes in gnomad4. There are 1927 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 56 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASAH1	NM_177924.5	c.*334G>A		3_prime_UTR_variant	14/14	ENST00000637790.2	NP_808592.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASAH1	ENST00000637790	c.*334G>A		3_prime_UTR_variant	14/14	1	NM_177924.5	ENSP00000490272.1

Frequencies

GnomAD3 genomes AF: 0.0253 AC: 3852 AN: 152148 Hom.: 56 Cov.: 32

Gnomad AFR AF: 0.0471

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.0565

Gnomad EAS AF: 0.00250

Gnomad SAS AF: 0.0354

Gnomad FIN AF: 0.0325

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0132

Gnomad OTH AF: 0.0234

GnomAD4 exome AF: 0.0195 AC: 2958 AN: 151310 Hom.: 52 Cov.: 0 AF XY: 0.0208 AC XY: 1703 AN XY: 81916

Gnomad4 AFR exome AF: 0.0502

Gnomad4 AMR exome AF: 0.0116

Gnomad4 ASJ exome AF: 0.0570

Gnomad4 EAS exome AF: 0.00387

Gnomad4 SAS exome AF: 0.0344

Gnomad4 FIN exome AF: 0.0253

Gnomad4 NFE exome AF: 0.0127

Gnomad4 OTH exome AF: 0.0198

GnomAD4 genome AF: 0.0253 AC: 3853 AN: 152266 Hom.: 56 Cov.: 32 AF XY: 0.0259 AC XY: 1927 AN XY: 74464

Gnomad4 AFR AF: 0.0470

Gnomad4 AMR AF: 0.0144

Gnomad4 ASJ AF: 0.0565

Gnomad4 EAS AF: 0.00251

Gnomad4 SAS AF: 0.0354

Gnomad4 FIN AF: 0.0325

Gnomad4 NFE AF: 0.0132

Gnomad4 OTH AF: 0.0232

Alfa AF: 0.00837 Hom.: 3

Bravo AF: 0.0243

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Farber lipogranulomatosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.9
DANN	Benign	0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs115127411; hg19: chr8-17914709;