8-18084296-G-A

Position:

• chr8-18084296-G-A

Variant summary

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

The NM_004315.6(ASAH1):​c.126+380C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0426 in 1,433,280 control chromosomes in the GnomAD database, including 1,767 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.061 (467 hom., cov: 33)
  • Exomes 𝑓: 0.040 (1300 hom.)
• Consequence: ASAH1 NM_004315.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.697

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=-0.8).
• BP6: Variant 8-18084296-G-A is Benign according to our data. Variant chr8-18084296-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 362395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASAH1	NM_004315.6	c.126+380C>T		intron_variant			NP_004306.3
ASAH1	NM_001127505.3	c.126+380C>T		intron_variant			NP_001120977.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASAH1	ENST00000381733.9	c.126+380C>T		intron_variant		1		ENSP00000371152.4
ASAH1	ENST00000314146.10	c.126+380C>T		intron_variant		1		ENSP00000326970.10
ASAH1	ENST00000637244.1	n.*281C>T		non_coding_transcript_exon_variant	1/14	1		ENSP00000490188.1

Frequencies

GnomAD3 genomes AF: 0.0612 AC: 9318 AN: 152174 Hom.: 461 Cov.: 33

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.0326

Gnomad ASJ AF: 0.0230

Gnomad EAS AF: 0.0516

Gnomad SAS AF: 0.0590

Gnomad FIN AF: 0.0103

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0365

Gnomad OTH AF: 0.0492

GnomAD4 exome AF: 0.0404 AC: 51729 AN: 1280988 Hom.: 1300 Cov.: 31 AF XY: 0.0408 AC XY: 25390 AN XY: 621964

Gnomad4 AFR exome AF: 0.133

Gnomad4 AMR exome AF: 0.0233

Gnomad4 ASJ exome AF: 0.0195

Gnomad4 EAS exome AF: 0.0762

Gnomad4 SAS exome AF: 0.0569

Gnomad4 FIN exome AF: 0.0124

Gnomad4 NFE exome AF: 0.0373

Gnomad4 OTH exome AF: 0.0392

GnomAD4 genome AF: 0.0613 AC: 9342 AN: 152292 Hom.: 467 Cov.: 33 AF XY: 0.0590 AC XY: 4397 AN XY: 74464

Gnomad4 AFR AF: 0.130

Gnomad4 AMR AF: 0.0326

Gnomad4 ASJ AF: 0.0230

Gnomad4 EAS AF: 0.0513

Gnomad4 SAS AF: 0.0591

Gnomad4 FIN AF: 0.0103

Gnomad4 NFE AF: 0.0365

Gnomad4 OTH AF: 0.0482

Alfa AF: 0.0604 Hom.: 62

Bravo AF: 0.0656

Asia WGS AF: 0.0510 AC: 176 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Farber lipogranulomatosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.7
DANN	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs35425490; hg19: chr8-17941805;