8-18064905-A-G

Position:

• chr8-18064905-A-G

Variant summary

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

The NM_177924.5(ASAH1):​c.383-374T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.628 in 176,556 control chromosomes in the GnomAD database, including 35,268 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 0.63 (30634 hom., cov: 33)
  • Exomes 𝑓: 0.61 (4634 hom.)
• Consequence: ASAH1 NM_177924.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.341

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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.674 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASAH1	NM_177924.5	c.383-374T>C		intron_variant		ENST00000637790.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASAH1	ENST00000637790.2	c.383-374T>C		intron_variant		1	NM_177924.5	P2

Frequencies

GnomAD3 genomes AF: 0.632 AC: 95969 AN: 151908 Hom.: 30616 Cov.: 33

Gnomad AFR AF: 0.681

Gnomad AMI AF: 0.595

Gnomad AMR AF: 0.550

Gnomad ASJ AF: 0.501

Gnomad EAS AF: 0.503

Gnomad SAS AF: 0.470

Gnomad FIN AF: 0.663

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.644

Gnomad OTH AF: 0.633

GnomAD4 exome AF: 0.605 AC: 14841 AN: 24530 Hom.: 4634 Cov.: 0 AF XY: 0.597 AC XY: 7578 AN XY: 12698

Gnomad4 AFR exome AF: 0.690

Gnomad4 AMR exome AF: 0.456

Gnomad4 ASJ exome AF: 0.528

Gnomad4 EAS exome AF: 0.500

Gnomad4 SAS exome AF: 0.449

Gnomad4 FIN exome AF: 0.683

Gnomad4 NFE exome AF: 0.650

Gnomad4 OTH exome AF: 0.607

GnomAD4 genome AF: 0.632 AC: 96037 AN: 152026 Hom.: 30634 Cov.: 33 AF XY: 0.626 AC XY: 46521 AN XY: 74330

Gnomad4 AFR AF: 0.681

Gnomad4 AMR AF: 0.550

Gnomad4 ASJ AF: 0.501

Gnomad4 EAS AF: 0.503

Gnomad4 SAS AF: 0.470

Gnomad4 FIN AF: 0.663

Gnomad4 NFE AF: 0.644

Gnomad4 OTH AF: 0.635

Alfa AF: 0.628 Hom.: 13766

Bravo AF: 0.622

Asia WGS AF: 0.533 AC: 1855 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	9.5
DANN	Benign	0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs7830490; hg19: chr8-17922414;