8-18084285-A-C

Position:

• chr8-18084285-A-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+391T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0621 in 1,436,972 control chromosomes in the GnomAD database, including 3,444 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.085 (794 hom., cov: 33)
  • Exomes 𝑓: 0.059 (2650 hom.)
• Consequence: ASAH1 NM_004315.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.345

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 (MetaRNN=0.0018770397).
• BP6: Variant 8-18084285-A-C is Benign according to our data. Variant chr8-18084285-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 362394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASAH1	NM_004315.6	c.126+391T>G		intron_variant			NP_004306.3
ASAH1	NM_001127505.3	c.126+391T>G		intron_variant			NP_001120977.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASAH1	ENST00000381733.9	c.126+391T>G		intron_variant		1		ENSP00000371152.4
ASAH1	ENST00000314146.10	c.126+391T>G		intron_variant		1		ENSP00000326970.10
ASAH1	ENST00000637244.1	n.*292T>G		non_coding_transcript_exon_variant	1/14	1		ENSP00000490188.1

Frequencies

GnomAD3 genomes AF: 0.0852 AC: 12965 AN: 152140 Hom.: 785 Cov.: 33

Gnomad AFR AF: 0.167

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.0423

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.0524

Gnomad SAS AF: 0.0627

Gnomad FIN AF: 0.0470

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0578

Gnomad OTH AF: 0.0675

GnomAD4 exome AF: 0.0593 AC: 76210 AN: 1284714 Hom.: 2650 Cov.: 31 AF XY: 0.0592 AC XY: 36925 AN XY: 624120

Gnomad4 AFR exome AF: 0.171

Gnomad4 AMR exome AF: 0.0305

Gnomad4 ASJ exome AF: 0.0261

Gnomad4 EAS exome AF: 0.0765

Gnomad4 SAS exome AF: 0.0605

Gnomad4 FIN exome AF: 0.0527

Gnomad4 NFE exome AF: 0.0571

Gnomad4 OTH exome AF: 0.0588

GnomAD4 genome AF: 0.0854 AC: 13005 AN: 152258 Hom.: 794 Cov.: 33 AF XY: 0.0837 AC XY: 6232 AN XY: 74446

Gnomad4 AFR AF: 0.167

Gnomad4 AMR AF: 0.0423

Gnomad4 ASJ AF: 0.0291

Gnomad4 EAS AF: 0.0521

Gnomad4 SAS AF: 0.0627

Gnomad4 FIN AF: 0.0470

Gnomad4 NFE AF: 0.0578

Gnomad4 OTH AF: 0.0663

Alfa AF: 0.0718 Hom.: 93

Bravo AF: 0.0877

TwinsUK AF: 0.0510 AC: 189

ALSPAC AF: 0.0506 AC: 195

Asia WGS AF: 0.0560 AC: 195 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

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

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	-0.76
CADD	Benign	1.6
DANN	Benign	0.53
DEOGEN2	Benign	0.025	T
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.098	T
MetaRNN	Benign	0.0019	T
GERP RS		2.4

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: rs34466559; hg19: chr8-17941794;