8-18065830-C-T

Position:

• chr8-18065830-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_177924.5(ASAH1):​c.383-1299G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.562 in 151,422 control chromosomes in the GnomAD database, including 24,631 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.56 (24631 hom., cov: 30)
  • Exomes 𝑓: 0.50 (0 hom.)
• Consequence: ASAH1 NM_177924.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.613

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.695 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASAH1	NM_177924.5	c.383-1299G>A		intron_variant		ENST00000637790.2	NP_808592.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASAH1	ENST00000637790.2	c.383-1299G>A		intron_variant		1	NM_177924.5	ENSP00000490272	P2

Frequencies

GnomAD3 genomes AF: 0.562 AC: 84997 AN: 151304 Hom.: 24611 Cov.: 30

Gnomad AFR AF: 0.702

Gnomad AMI AF: 0.425

Gnomad AMR AF: 0.472

Gnomad ASJ AF: 0.388

Gnomad EAS AF: 0.497

Gnomad SAS AF: 0.469

Gnomad FIN AF: 0.551

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.521

Gnomad OTH AF: 0.529

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

Gnomad4 NFE exome AF: 0.500

GnomAD4 genome AF: 0.562 AC: 85061 AN: 151420 Hom.: 24631 Cov.: 30 AF XY: 0.559 AC XY: 41288 AN XY: 73912

Gnomad4 AFR AF: 0.702

Gnomad4 AMR AF: 0.472

Gnomad4 ASJ AF: 0.388

Gnomad4 EAS AF: 0.497

Gnomad4 SAS AF: 0.467

Gnomad4 FIN AF: 0.551

Gnomad4 NFE AF: 0.521

Gnomad4 OTH AF: 0.532

Alfa AF: 0.543 Hom.: 3229

Bravo AF: 0.556

Asia WGS AF: 0.521 AC: 1806 AN: 3462

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.9
DANN	Benign	0.24

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: rs4377998; hg19: chr8-17923339;