rs12547845

Positions:

• chr8-18071411-T-C
• chr8-18071411-T-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.126-21A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.479 in 1,467,130 control chromosomes in the GnomAD database, including 172,590 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14933 hom., cov: 31)
  • Exomes 𝑓: 0.48 (157657 hom.)
• Consequence: ASAH1 NM_177924.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.776

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=-0.83).
• BP6: Variant 8-18071411-T-C is Benign according to our data. Variant chr8-18071411-T-C is described in ClinVar as [Benign]. Clinvar id is 259277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.519 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASAH1	NM_177924.5	c.126-21A>G		intron_variant		ENST00000637790.2	NP_808592.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASAH1	ENST00000637790.2	c.126-21A>G		intron_variant		1	NM_177924.5	ENSP00000490272	P2

Frequencies

GnomAD3 genomes AF: 0.430 AC: 65227 AN: 151782 Hom.: 14917 Cov.: 31

Gnomad AFR AF: 0.276

Gnomad AMI AF: 0.577

Gnomad AMR AF: 0.529

Gnomad ASJ AF: 0.619

Gnomad EAS AF: 0.381

Gnomad SAS AF: 0.523

Gnomad FIN AF: 0.420

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.487

Gnomad OTH AF: 0.465

GnomAD3 exomes AF: 0.494 AC: 104458 AN: 211334 Hom.: 26750 AF XY: 0.497 AC XY: 56088 AN XY: 112832

Gnomad AFR exome AF: 0.272

Gnomad AMR exome AF: 0.655

Gnomad ASJ exome AF: 0.609

Gnomad EAS exome AF: 0.366

Gnomad SAS exome AF: 0.537

Gnomad FIN exome AF: 0.412

Gnomad NFE exome AF: 0.488

Gnomad OTH exome AF: 0.502

GnomAD4 exome AF: 0.485 AC: 637842 AN: 1315230 Hom.: 157657 Cov.: 20 AF XY: 0.488 AC XY: 320838 AN XY: 657758

Gnomad4 AFR exome AF: 0.266

Gnomad4 AMR exome AF: 0.638

Gnomad4 ASJ exome AF: 0.610

Gnomad4 EAS exome AF: 0.403

Gnomad4 SAS exome AF: 0.538

Gnomad4 FIN exome AF: 0.412

Gnomad4 NFE exome AF: 0.485

Gnomad4 OTH exome AF: 0.478

GnomAD4 genome AF: 0.430 AC: 65282 AN: 151900 Hom.: 14933 Cov.: 31 AF XY: 0.431 AC XY: 31960 AN XY: 74236

Gnomad4 AFR AF: 0.276

Gnomad4 AMR AF: 0.529

Gnomad4 ASJ AF: 0.619

Gnomad4 EAS AF: 0.382

Gnomad4 SAS AF: 0.525

Gnomad4 FIN AF: 0.420

Gnomad4 NFE AF: 0.487

Gnomad4 OTH AF: 0.461

Alfa AF: 0.478 Hom.: 3344

Bravo AF: 0.434

Asia WGS AF: 0.418 AC: 1453 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 22, 2015	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.0
DANN	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs12547845; hg19: chr8-17928920; COSMIC: COSV50504232; COSMIC: COSV50504232;