rs3753116

Variant names:

• chr8-18073490-A-G
• rs3753116
• NM_177924.5:c.125+2051T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_177924.5(ASAH1):​c.125+2051T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.429 in 152,046 control chromosomes in the GnomAD database, including 14,926 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.43 (14926 hom., cov: 32)
• Consequence: ASAH1 NM_177924.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.310
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 8-18073490-A-G is Benign according to our data. Variant chr8-18073490-A-G is described in ClinVar as Benign. ClinVar VariationId is 678021.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.519 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASAH1	NM_177924.5	c.125+2051T>C		intron_variant	Intron 2 of 13	ENST00000637790.2	NP_808592.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASAH1	ENST00000637790.2	c.125+2051T>C		intron_variant	Intron 2 of 13	1	NM_177924.5	ENSP00000490272.1

Frequencies

GnomAD3 genomes AF: 0.429 AC: 65246 AN: 151928 Hom.: 14910 Cov.: 32

Gnomad AFR AF: 0.277

Gnomad AMI AF: 0.574

Gnomad AMR AF: 0.528

Gnomad ASJ AF: 0.615

Gnomad EAS AF: 0.377

Gnomad SAS AF: 0.522

Gnomad FIN AF: 0.420

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.486

Gnomad OTH AF: 0.464

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.429 AC: 65302 AN: 152046 Hom.: 14926 Cov.: 32 AF XY: 0.430 AC XY: 31970 AN XY: 74312

African (AFR) AF: 0.277 AC: 11493 AN: 41462

American (AMR) AF: 0.529 AC: 8084 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.615 AC: 2135 AN: 3472

East Asian (EAS) AF: 0.377 AC: 1949 AN: 5164

South Asian (SAS) AF: 0.524 AC: 2523 AN: 4818

European-Finnish (FIN) AF: 0.420 AC: 4439 AN: 10564

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.486 AC: 33060 AN: 67966

Other (OTH) AF: 0.461 AC: 974 AN: 2112

Alfa AF: 0.464 Hom.: 2961

Bravo AF: 0.434

Asia WGS AF: 0.415 AC: 1442 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.4
DANN	Benign	0.61
PhyloP100		0.31
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: rs3753116; hg19: chr8-17930999;