ENST00000314146.10:c.187G>A

Variant names:

• chr8-18073263-C-T
• rs3753115
• ENST00000314146.10:c.187G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The ENST00000314146.10(ASAH1):​c.187G>A​(p.Val63Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.464 in 1,499,158 control chromosomes in the GnomAD database, including 172,931 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14867 hom., cov: 32)
  • Exomes 𝑓: 0.47 (158064 hom.)
• Consequence: ASAH1 ENST00000314146.10 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.03
• Publications: 29 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 -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in ENST00000314146.10
• BP4: Computational evidence support a benign effect (MetaRNN=3.0002971E-5).
• BP6: Variant 8-18073263-C-T is Benign according to our data. Variant chr8-18073263-C-T is described in ClinVar as Benign. ClinVar VariationId is 402397.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.518 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000314146.10. 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.126-1873G>A		intron	N/A	NP_808592.2
	ASAH1	NM_001127505.3		c.187G>A	p.Val63Ile	missense	Exon 3 of 14	NP_001120977.1
	ASAH1	NM_004315.6		c.174-1873G>A		intron	N/A	NP_004306.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASAH1	ENST00000314146.10	TSL:1	c.187G>A	p.Val63Ile	missense	Exon 3 of 14	ENSP00000326970.10
	ASAH1	ENST00000637790.2	TSL:1 MANE Select	c.126-1873G>A		intron	N/A	ENSP00000490272.1
	ASAH1	ENST00000381733.9	TSL:1	c.174-1873G>A		intron	N/A	ENSP00000371152.4

Frequencies

GnomAD3 genomes AF: 0.428 AC: 65074 AN: 151910 Hom.: 14851 Cov.: 32

Gnomad AFR AF: 0.276

Gnomad AMI AF: 0.628

Gnomad AMR AF: 0.527

Gnomad ASJ AF: 0.615

Gnomad EAS AF: 0.368

Gnomad SAS AF: 0.510

Gnomad FIN AF: 0.420

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.486

Gnomad OTH AF: 0.461

GnomAD2 exomes AF: 0.470 AC: 108245 AN: 230130 AF XY: 0.472

Gnomad AFR exome AF: 0.254

Gnomad AMR exome AF: 0.639

Gnomad ASJ exome AF: 0.602

Gnomad EAS exome AF: 0.337

Gnomad FIN exome AF: 0.405

Gnomad NFE exome AF: 0.465

Gnomad OTH exome AF: 0.477

GnomAD4 exome AF: 0.467 AC: 629736 AN: 1347130 Hom.: 158064 Cov.: 31 AF XY: 0.470 AC XY: 315199 AN XY: 670602

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.250 AC: 7941 AN: 31784

American (AMR) AF: 0.623 AC: 24737 AN: 39676

Ashkenazi Jewish (ASJ) AF: 0.597 AC: 14543 AN: 24376

East Asian (EAS) AF: 0.381 AC: 14388 AN: 37722

South Asian (SAS) AF: 0.517 AC: 41929 AN: 81040

European-Finnish (FIN) AF: 0.400 AC: 20232 AN: 50576

Middle Eastern (MID) AF: 0.473 AC: 2584 AN: 5462

European-Non Finnish (NFE) AF: 0.468 AC: 477808 AN: 1020694

Other (OTH) AF: 0.458 AC: 25574 AN: 55800

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.428 AC: 65129 AN: 152028 Hom.: 14867 Cov.: 32 AF XY: 0.429 AC XY: 31871 AN XY: 74310

African (AFR) AF: 0.276 AC: 11439 AN: 41432

American (AMR) AF: 0.528 AC: 8068 AN: 15286

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

East Asian (EAS) AF: 0.368 AC: 1906 AN: 5174

South Asian (SAS) AF: 0.512 AC: 2466 AN: 4818

European-Finnish (FIN) AF: 0.420 AC: 4426 AN: 10536

Middle Eastern (MID) AF: 0.425 AC: 125 AN: 294

European-Non Finnish (NFE) AF: 0.486 AC: 33024 AN: 67992

Other (OTH) AF: 0.458 AC: 967 AN: 2112

Alfa AF: 0.475 Hom.: 46486

Bravo AF: 0.433

TwinsUK AF: 0.480 AC: 1781

ALSPAC AF: 0.488 AC: 1880

ESP6500AA AF: 0.281 AC: 880

ESP6500EA AF: 0.487 AC: 3484

ExAC AF: 0.464 AC: 55816

Asia WGS AF: 0.404 AC: 1405 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 47% of total chromosomes in ExAC

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

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.

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Spinal muscular atrophy-progressive myoclonic epilepsy syndrome Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Farber lipogranulomatosis Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	1.1
DANN	Benign	0.30
DEOGEN2	Benign	0.0028	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0087	N
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.000030	T
MetaSVM	Benign	-0.93	T
PhyloP100		-1.0
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.043
Sift	Benign	0.29	T
Sift4G	Benign	0.38	T
Vest4		0.024
ClinPred		0.0022	T
GERP RS		-1.6
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: rs3753115; hg19: chr8-17930772; COSMIC: COSV50502107; COSMIC: COSV50502107;