8-18075949-C-T

Variant names:

• chr8-18075949-C-T
• rs10105871
• NM_177924.5:c.79-362G>A

Variant summary

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

The NM_177924.5(ASAH1):​c.79-362G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.57 in 336,136 control chromosomes in the GnomAD database, including 55,965 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 0.57 (25424 hom., cov: 32)
  • Exomes 𝑓: 0.57 (30541 hom.)
• Consequence: ASAH1 NM_177924.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.903
• Publications: 6 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=-1.0).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.609 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177924.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASAH1	NM_177924.5	MANE Select	c.79-362G>A		intron	N/A	NP_808592.2
	ASAH1	NM_004315.6		c.127-362G>A		intron	N/A	NP_004306.3
	ASAH1	NM_001127505.3		c.127-362G>A		intron	N/A	NP_001120977.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASAH1	ENST00000637790.2	TSL:1 MANE Select	c.79-362G>A		intron	N/A	ENSP00000490272.1
	ASAH1	ENST00000381733.9	TSL:1	c.127-362G>A		intron	N/A	ENSP00000371152.4
	ASAH1	ENST00000314146.10	TSL:1	c.127-362G>A		intron	N/A	ENSP00000326970.10

Frequencies

GnomAD3 genomes AF: 0.573 AC: 87098 AN: 151888 Hom.: 25423 Cov.: 32

Gnomad AFR AF: 0.578

Gnomad AMI AF: 0.610

Gnomad AMR AF: 0.459

Gnomad ASJ AF: 0.539

Gnomad EAS AF: 0.317

Gnomad SAS AF: 0.478

Gnomad FIN AF: 0.648

Gnomad MID AF: 0.560

Gnomad NFE AF: 0.614

Gnomad OTH AF: 0.534

GnomAD4 exome AF: 0.567 AC: 104420 AN: 184130 Hom.: 30541 Cov.: 0 AF XY: 0.557 AC XY: 56477 AN XY: 101468

African (AFR) AF: 0.573 AC: 2872 AN: 5012

American (AMR) AF: 0.418 AC: 2788 AN: 6664

Ashkenazi Jewish (ASJ) AF: 0.534 AC: 2404 AN: 4498

East Asian (EAS) AF: 0.316 AC: 2378 AN: 7534

South Asian (SAS) AF: 0.490 AC: 17067 AN: 34852

European-Finnish (FIN) AF: 0.656 AC: 5606 AN: 8542

Middle Eastern (MID) AF: 0.561 AC: 369 AN: 658

European-Non Finnish (NFE) AF: 0.613 AC: 65716 AN: 107258

Other (OTH) AF: 0.573 AC: 5220 AN: 9112

GnomAD4 genome AF: 0.573 AC: 87132 AN: 152006 Hom.: 25424 Cov.: 32 AF XY: 0.568 AC XY: 42228 AN XY: 74298

African (AFR) AF: 0.578 AC: 23930 AN: 41436

American (AMR) AF: 0.459 AC: 7010 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.539 AC: 1871 AN: 3472

East Asian (EAS) AF: 0.316 AC: 1630 AN: 5156

South Asian (SAS) AF: 0.475 AC: 2285 AN: 4806

European-Finnish (FIN) AF: 0.648 AC: 6838 AN: 10560

Middle Eastern (MID) AF: 0.548 AC: 161 AN: 294

European-Non Finnish (NFE) AF: 0.614 AC: 41715 AN: 67974

Other (OTH) AF: 0.538 AC: 1138 AN: 2116

Alfa AF: 0.592 Hom.: 17123

Bravo AF: 0.557

Asia WGS AF: 0.423 AC: 1471 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.44
DANN	Benign	0.17
PhyloP100		-0.90
PromoterAI		0.0060	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: rs10105871; hg19: chr8-17933458; COSMIC: COSV50505962; COSMIC: COSV50505962;