8-18084530-C-T

Position:

• chr8-18084530-C-T

Variant summary

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

The NM_004315.6(ASAH1):​c.126+146G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0549 in 1,418,792 control chromosomes in the GnomAD database, including 2,704 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (605 hom., cov: 33)
  • Exomes 𝑓: 0.052 (2099 hom.)
• Consequence: ASAH1 NM_004315.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.440

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-AS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 8-18084530-C-T is Benign according to our data. Variant chr8-18084530-C-T is described in ClinVar as [Benign]. Clinvar id is 1239600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASAH1	NM_004315.6	c.126+146G>A		intron_variant			NP_004306.3
ASAH1	NM_001127505.3	c.126+146G>A		intron_variant			NP_001120977.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASAH1	ENST00000381733.9	c.126+146G>A		intron_variant		1		ENSP00000371152.4
ASAH1	ENST00000314146.10	c.126+146G>A		intron_variant		1		ENSP00000326970.10
ASAH1	ENST00000637244.1	n.*47G>A		non_coding_transcript_exon_variant	1/14	1		ENSP00000490188.1

Frequencies

GnomAD3 genomes AF: 0.0754 AC: 11468 AN: 152112 Hom.: 600 Cov.: 33

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.168

Gnomad AMR AF: 0.0389

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.0523

Gnomad SAS AF: 0.0626

Gnomad FIN AF: 0.0351

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0524

Gnomad OTH AF: 0.0588

GnomAD4 exome AF: 0.0524 AC: 66369 AN: 1266562 Hom.: 2099 Cov.: 18 AF XY: 0.0525 AC XY: 33044 AN XY: 629494

Gnomad4 AFR exome AF: 0.146

Gnomad4 AMR exome AF: 0.0233

Gnomad4 ASJ exome AF: 0.0236

Gnomad4 EAS exome AF: 0.0747

Gnomad4 SAS exome AF: 0.0593

Gnomad4 FIN exome AF: 0.0341

Gnomad4 NFE exome AF: 0.0509

Gnomad4 OTH exome AF: 0.0509

GnomAD4 genome AF: 0.0755 AC: 11494 AN: 152230 Hom.: 605 Cov.: 33 AF XY: 0.0736 AC XY: 5478 AN XY: 74438

Gnomad4 AFR AF: 0.145

Gnomad4 AMR AF: 0.0389

Gnomad4 ASJ AF: 0.0248

Gnomad4 EAS AF: 0.0520

Gnomad4 SAS AF: 0.0627

Gnomad4 FIN AF: 0.0351

Gnomad4 NFE AF: 0.0524

Gnomad4 OTH AF: 0.0577

Alfa AF: 0.0736 Hom.: 85

Bravo AF: 0.0781

Asia WGS AF: 0.0530 AC: 185 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2018	- -
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	-0.54
CADD	Benign	5.2
DANN	Uncertain	0.97

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs17436109; hg19: chr8-17942039;