rs6586684

Positions:

• chr8-18067822-A-G
• chr8-18067822-A-T

Variant summary

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

The NM_177924.5(ASAH1):​c.304-524T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.347 in 152,168 control chromosomes in the GnomAD database, including 9,559 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 0.35 (9559 hom., cov: 32)
  • Exomes 𝑓: 0.14 (0 hom.)
• Consequence: ASAH1 NM_177924.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.189

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=-0.78).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.485 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASAH1	NM_177924.5	c.304-524T>C		intron_variant		ENST00000637790.2	NP_808592.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASAH1	ENST00000637790.2	c.304-524T>C		intron_variant		1	NM_177924.5	ENSP00000490272	P2

Frequencies

GnomAD3 genomes AF: 0.347 AC: 52818 AN: 152010 Hom.: 9550 Cov.: 32

Gnomad AFR AF: 0.262

Gnomad AMI AF: 0.407

Gnomad AMR AF: 0.443

Gnomad ASJ AF: 0.508

Gnomad EAS AF: 0.377

Gnomad SAS AF: 0.501

Gnomad FIN AF: 0.307

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.363

Gnomad OTH AF: 0.354

GnomAD4 exome AF: 0.143 AC: 6 AN: 42 Hom.: 0 Cov.: 0 AF XY: 0.0938 AC XY: 3 AN XY: 32

Gnomad4 EAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.139

GnomAD4 genome AF: 0.348 AC: 52865 AN: 152126 Hom.: 9559 Cov.: 32 AF XY: 0.351 AC XY: 26071 AN XY: 74372

Gnomad4 AFR AF: 0.262

Gnomad4 AMR AF: 0.443

Gnomad4 ASJ AF: 0.508

Gnomad4 EAS AF: 0.377

Gnomad4 SAS AF: 0.502

Gnomad4 FIN AF: 0.307

Gnomad4 NFE AF: 0.363

Gnomad4 OTH AF: 0.351

Alfa AF: 0.368 Hom.: 2357

Bravo AF: 0.356

Asia WGS AF: 0.398 AC: 1383 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.2
DANN	Benign	0.83

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: rs6586684; hg19: chr8-17925331;