rs2427746

chr8-18069675-A-G

Variant summary

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

The NM_177924.5(ASAH1):c.303+117T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.387 in 705,090 control chromosomes in the GnomAD database, including 55,828 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (11122 hom., cov: 32)
  • Exomes 𝑓: 0.39 (44706 hom.)
• Consequence: ASAH1 NM_177924.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.340

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 8-18069675-A-G is Benign according to our data. Variant chr8-18069675-A-G is described in ClinVar as [Benign]. Clinvar id is 678030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.442 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASAH1	NM_177924.5	c.303+117T>C		intron_variant		ENST00000637790.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASAH1	ENST00000637790.2	c.303+117T>C		intron_variant		1	NM_177924.5	P2

Frequencies

GnomAD3 genomes AF: 0.362 AC: 55057 AN: 151976 Hom.: 11104 Cov.: 32

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.569

Gnomad AMR AF: 0.427

Gnomad ASJ AF: 0.520

Gnomad EAS AF: 0.320

Gnomad SAS AF: 0.456

Gnomad FIN AF: 0.372

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.445

Gnomad OTH AF: 0.402

GnomAD4 exome AF: 0.394 AC: 217812 AN: 552998 Hom.: 44706 Cov.: 7 AF XY: 0.399 AC XY: 118201 AN XY: 296586

Gnomad4 AFR exome AF: 0.148

Gnomad4 AMR exome AF: 0.444

Gnomad4 ASJ exome AF: 0.473

Gnomad4 EAS exome AF: 0.333

Gnomad4 SAS exome AF: 0.436

Gnomad4 FIN exome AF: 0.333

Gnomad4 NFE exome AF: 0.403

Gnomad4 OTH exome AF: 0.386

GnomAD4 genome AF: 0.362 AC: 55097 AN: 152092 Hom.: 11122 Cov.: 32 AF XY: 0.363 AC XY: 26945 AN XY: 74330

Gnomad4 AFR AF: 0.175

Gnomad4 AMR AF: 0.427

Gnomad4 ASJ AF: 0.520

Gnomad4 EAS AF: 0.320

Gnomad4 SAS AF: 0.458

Gnomad4 FIN AF: 0.372

Gnomad4 NFE AF: 0.445

Gnomad4 OTH AF: 0.399

Alfa AF: 0.417 Hom.: 4914

Bravo AF: 0.360

Asia WGS AF: 0.373 AC: 1298 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spinal muscular atrophy-progressive myoclonic epilepsy syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Farber lipogranulomatosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	5.4
Dann	Benign	0.58

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: rs2427746; hg19: chr8-17927184;