8-18061477-A-G

Position:

• chr8-18061477-A-G

Variant summary

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

The ENST00000637790.2(ASAH1):​c.704-19T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.266 in 1,596,606 control chromosomes in the GnomAD database, including 59,237 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4341 hom., cov: 32)
  • Exomes 𝑓: 0.27 (54896 hom.)
• Consequence: ASAH1 ENST00000637790.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.596

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]

ASAH1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 8-18061477-A-G is Benign according to our data. Variant chr8-18061477-A-G is described in ClinVar as [Benign]. Clinvar id is 259282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-18061477-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.353 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASAH1	NM_177924.5	c.704-19T>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.704-19T>C		intron_variant		1	NM_177924.5	ENSP00000490272.1

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34472 AN: 152042 Hom.: 4331 Cov.: 32

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.281

Gnomad AMR AF: 0.300

Gnomad ASJ AF: 0.321

Gnomad EAS AF: 0.315

Gnomad SAS AF: 0.367

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.260

Gnomad OTH AF: 0.245

GnomAD3 exomes AF: 0.281 AC: 70697 AN: 251196 Hom.: 11064 AF XY: 0.283 AC XY: 38356 AN XY: 135760

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.429

Gnomad ASJ exome AF: 0.304

Gnomad EAS exome AF: 0.296

Gnomad SAS exome AF: 0.365

Gnomad FIN exome AF: 0.192

Gnomad NFE exome AF: 0.252

Gnomad OTH exome AF: 0.267

GnomAD4 exome AF: 0.270 AC: 389731 AN: 1444446 Hom.: 54896 Cov.: 30 AF XY: 0.273 AC XY: 196346 AN XY: 719954

Gnomad4 AFR exome AF: 0.104

Gnomad4 AMR exome AF: 0.413

Gnomad4 ASJ exome AF: 0.306

Gnomad4 EAS exome AF: 0.343

Gnomad4 SAS exome AF: 0.365

Gnomad4 FIN exome AF: 0.196

Gnomad4 NFE exome AF: 0.262

Gnomad4 OTH exome AF: 0.269

GnomAD4 genome AF: 0.227 AC: 34503 AN: 152160 Hom.: 4341 Cov.: 32 AF XY: 0.230 AC XY: 17120 AN XY: 74396

Gnomad4 AFR AF: 0.113

Gnomad4 AMR AF: 0.301

Gnomad4 ASJ AF: 0.321

Gnomad4 EAS AF: 0.315

Gnomad4 SAS AF: 0.367

Gnomad4 FIN AF: 0.204

Gnomad4 NFE AF: 0.260

Gnomad4 OTH AF: 0.243

Alfa AF: 0.257 Hom.: 10966

Bravo AF: 0.230

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2018	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	-0.89
CADD	Benign	5.6
DANN	Benign	0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs17515291; hg19: chr8-17918986;