8-18065830-C-T

Variant names:

• chr8-18065830-C-T
• rs4377998
• NM_177924.5:c.383-1299G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004315.6(ASAH1):​c.431-1299G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.562 in 151,422 control chromosomes in the GnomAD database, including 24,631 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.56 (24631 hom., cov: 30)
  • Exomes 𝑓: 0.50 (0 hom.)
• Consequence: ASAH1 NM_004315.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.613
• Publications: 2 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 Gene-Disease associations (from GenCC):

• ASAH1-related sphingolipidosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Farber lipogranulomatosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• spinal muscular atrophy-progressive myoclonic epilepsy syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.695 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_177924.5	MANE Select	c.383-1299G>A		intron	N/A	NP_808592.2
	ASAH1	NM_004315.6		c.431-1299G>A		intron	N/A	NP_004306.3
	ASAH1	NM_001127505.3		c.365-1299G>A		intron	N/A	NP_001120977.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASAH1	ENST00000637790.2	TSL:1 MANE Select	c.383-1299G>A		intron	N/A	ENSP00000490272.1
	ASAH1	ENST00000381733.9	TSL:1	c.431-1299G>A		intron	N/A	ENSP00000371152.4
	ASAH1	ENST00000314146.10	TSL:1	c.365-1299G>A		intron	N/A	ENSP00000326970.10

Frequencies

GnomAD3 genomes AF: 0.562 AC: 84997 AN: 151304 Hom.: 24611 Cov.: 30

Gnomad AFR AF: 0.702

Gnomad AMI AF: 0.425

Gnomad AMR AF: 0.472

Gnomad ASJ AF: 0.388

Gnomad EAS AF: 0.497

Gnomad SAS AF: 0.469

Gnomad FIN AF: 0.551

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.521

Gnomad OTH AF: 0.529

GnomAD4 exome AF: 0.500 AC: 1 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.500 AC XY: 1 AN XY: 2

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 1 AN: 2

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.562 AC: 85061 AN: 151420 Hom.: 24631 Cov.: 30 AF XY: 0.559 AC XY: 41288 AN XY: 73912

African (AFR) AF: 0.702 AC: 28988 AN: 41296

American (AMR) AF: 0.472 AC: 7178 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.388 AC: 1342 AN: 3462

East Asian (EAS) AF: 0.497 AC: 2552 AN: 5134

South Asian (SAS) AF: 0.467 AC: 2247 AN: 4812

European-Finnish (FIN) AF: 0.551 AC: 5727 AN: 10388

Middle Eastern (MID) AF: 0.561 AC: 165 AN: 294

European-Non Finnish (NFE) AF: 0.521 AC: 35358 AN: 67816

Other (OTH) AF: 0.532 AC: 1118 AN: 2100

Alfa AF: 0.579 Hom.: 9940

Bravo AF: 0.556

Asia WGS AF: 0.521 AC: 1806 AN: 3462

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.9
DANN	Benign	0.24
PhyloP100		-0.61
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: rs4377998; hg19: chr8-17923339;