chr8-18084412-G-C

Position:

• chr8-18084412-G-C

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+264C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0374 in 1,390,446 control chromosomes in the GnomAD database, including 1,154 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (114 hom., cov: 33)
  • Exomes 𝑓: 0.038 (1040 hom.)
• Consequence: ASAH1 NM_004315.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.382

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=-0.86).
• BP6: Variant 8-18084412-G-C is Benign according to our data. Variant chr8-18084412-G-C is described in ClinVar as [Benign]. Clinvar id is 1236392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0594 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASAH1	NM_004315.6	c.126+264C>G		intron_variant			NP_004306.3
ASAH1	NM_001127505.3	c.126+264C>G		intron_variant			NP_001120977.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASAH1	ENST00000381733.9	c.126+264C>G		intron_variant		1		ENSP00000371152.4
ASAH1	ENST00000314146.10	c.126+264C>G		intron_variant		1		ENSP00000326970.10
ASAH1	ENST00000637244.1	n.*165C>G		non_coding_transcript_exon_variant	1/14	1		ENSP00000490188.1

Frequencies

GnomAD3 genomes AF: 0.0311 AC: 4728 AN: 152102 Hom.: 114 Cov.: 33

Gnomad AFR AF: 0.00859

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.0234

Gnomad ASJ AF: 0.0712

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0539

Gnomad FIN AF: 0.0519

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0409

Gnomad OTH AF: 0.0291

GnomAD4 exome AF: 0.0382 AC: 47276 AN: 1238226 Hom.: 1040 Cov.: 25 AF XY: 0.0391 AC XY: 23436 AN XY: 599412

Gnomad4 AFR exome AF: 0.00814

Gnomad4 AMR exome AF: 0.0211

Gnomad4 ASJ exome AF: 0.0679

Gnomad4 EAS exome AF: 0.000350

Gnomad4 SAS exome AF: 0.0611

Gnomad4 FIN exome AF: 0.0528

Gnomad4 NFE exome AF: 0.0382

Gnomad4 OTH exome AF: 0.0374

GnomAD4 genome AF: 0.0310 AC: 4726 AN: 152220 Hom.: 114 Cov.: 33 AF XY: 0.0314 AC XY: 2337 AN XY: 74410

Gnomad4 AFR AF: 0.00857

Gnomad4 AMR AF: 0.0233

Gnomad4 ASJ AF: 0.0712

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0537

Gnomad4 FIN AF: 0.0519

Gnomad4 NFE AF: 0.0409

Gnomad4 OTH AF: 0.0293

Alfa AF: 0.0157 Hom.: 5

Bravo AF: 0.0274

Asia WGS AF: 0.0290 AC: 103 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	-0.86
CADD	Benign	0.98
DANN	Benign	0.35

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs142262157; hg19: chr8-17941921;