8-18084285-A-C

Variant names:

• chr8-18084285-A-C
• rs34466559
• ENST00000381733.9:c.126+391T>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 publications found

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:55603): (ASAH1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004315.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASAH1	NM_004315.6		c.126+391T>G		intron	N/A	NP_004306.3
	ASAH1	NM_001127505.3		c.126+391T>G		intron	N/A	NP_001120977.1	Q13510-3
	ASAH1	NM_177924.5	MANE Select	c.-227T>G		upstream_gene	N/A	NP_808592.2	Q13510-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASAH1	ENST00000381733.9	TSL:1	c.126+391T>G		intron	N/A	ENSP00000371152.4	Q13510-2
	ASAH1	ENST00000314146.10	TSL:1	c.126+391T>G		intron	N/A	ENSP00000326970.10	Q13510-3
	ASAH1	ENST00000637244.1	TSL:1	n.*292T>G		non_coding_transcript_exon	Exon 1 of 14	ENSP00000490188.1	A0A1B0GUP1

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

African (AFR) AF: 0.171 AC: 4815 AN: 28170

American (AMR) AF: 0.0305 AC: 611 AN: 20052

Ashkenazi Jewish (ASJ) AF: 0.0261 AC: 493 AN: 18860

East Asian (EAS) AF: 0.0765 AC: 2655 AN: 34726

South Asian (SAS) AF: 0.0605 AC: 3801 AN: 62778

European-Finnish (FIN) AF: 0.0527 AC: 1555 AN: 29528

Middle Eastern (MID) AF: 0.0333 AC: 120 AN: 3604

European-Non Finnish (NFE) AF: 0.0571 AC: 59022 AN: 1033646

Other (OTH) AF: 0.0588 AC: 3138 AN: 53350

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

African (AFR) AF: 0.167 AC: 6953 AN: 41534

American (AMR) AF: 0.0423 AC: 647 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0291 AC: 101 AN: 3468

East Asian (EAS) AF: 0.0521 AC: 269 AN: 5162

South Asian (SAS) AF: 0.0627 AC: 303 AN: 4832

European-Finnish (FIN) AF: 0.0470 AC: 499 AN: 10616

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0578 AC: 3933 AN: 68022

Other (OTH) AF: 0.0663 AC: 140 AN: 2112

Alfa AF: 0.0734 Hom.: 101

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Farber lipogranulomatosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
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
PhyloP100		-0.34
GERP RS		2.4
PromoterAI		0.12	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs34466559; hg19: chr8-17941794;