8-18084625-A-G

Position:

• chr8-18084625-A-G

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+51T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0385 in 1,609,454 control chromosomes in the GnomAD database, including 1,415 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (123 hom., cov: 33)
  • Exomes 𝑓: 0.039 (1292 hom.)
• Consequence: ASAH1 NM_004315.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.249

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-AS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 8-18084625-A-G is Benign according to our data. Variant chr8-18084625-A-G is described in ClinVar as [Benign]. Clinvar id is 1295818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-18084625-A-G is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0588 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASAH1	NM_004315.6	c.126+51T>C		intron_variant			NP_004306.3
ASAH1	NM_001127505.3	c.126+51T>C		intron_variant			NP_001120977.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASAH1	ENST00000381733.9	c.126+51T>C		intron_variant		1		ENSP00000371152.4
ASAH1	ENST00000314146.10	c.126+51T>C		intron_variant		1		ENSP00000326970.10
ASAH1	ENST00000637244.1	n.177T>C		non_coding_transcript_exon_variant	1/14	1		ENSP00000490188.1

Frequencies

GnomAD3 genomes AF: 0.0337 AC: 5132 AN: 152184 Hom.: 122 Cov.: 33

Gnomad AFR AF: 0.0168

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.0244

Gnomad ASJ AF: 0.0778

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0536

Gnomad FIN AF: 0.0518

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0412

Gnomad OTH AF: 0.0316

GnomAD3 exomes AF: 0.0386 AC: 9419 AN: 243832 Hom.: 224 AF XY: 0.0412 AC XY: 5425 AN XY: 131792

Gnomad AFR exome AF: 0.0168

Gnomad AMR exome AF: 0.0179

Gnomad ASJ exome AF: 0.0740

Gnomad EAS exome AF: 0.000879

Gnomad SAS exome AF: 0.0605

Gnomad FIN exome AF: 0.0510

Gnomad NFE exome AF: 0.0424

Gnomad OTH exome AF: 0.0484

GnomAD4 exome AF: 0.0390 AC: 56790 AN: 1457152 Hom.: 1292 Cov.: 31 AF XY: 0.0400 AC XY: 28988 AN XY: 724448

Gnomad4 AFR exome AF: 0.0164

Gnomad4 AMR exome AF: 0.0192

Gnomad4 ASJ exome AF: 0.0752

Gnomad4 EAS exome AF: 0.000429

Gnomad4 SAS exome AF: 0.0602

Gnomad4 FIN exome AF: 0.0524

Gnomad4 NFE exome AF: 0.0386

Gnomad4 OTH exome AF: 0.0401

GnomAD4 genome AF: 0.0338 AC: 5143 AN: 152302 Hom.: 123 Cov.: 33 AF XY: 0.0340 AC XY: 2531 AN XY: 74482

Gnomad4 AFR AF: 0.0171

Gnomad4 AMR AF: 0.0244

Gnomad4 ASJ AF: 0.0778

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0535

Gnomad4 FIN AF: 0.0518

Gnomad4 NFE AF: 0.0412

Gnomad4 OTH AF: 0.0317

Alfa AF: 0.0405 Hom.: 23

Bravo AF: 0.0304

Asia WGS AF: 0.0310 AC: 108 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.5
DANN	Benign	0.50

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs10106608; hg19: chr8-17942134;