rs1049874

chr8-18069818-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_177924.5(ASAH1):c.277A>G(p.Ile93Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.475 in 1,562,986 control chromosomes in the GnomAD database, including 181,906 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14946 hom., cov: 32)
  • Exomes 𝑓: 0.48 (166960 hom.)
• Consequence: ASAH1 NM_177924.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.77

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.8589424E-6).
• BP6: Variant 8-18069818-T-C is Benign according to our data. Variant chr8-18069818-T-C is described in ClinVar as [Benign]. Clinvar id is 197389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-18069818-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.518 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASAH1	NM_177924.5	c.277A>G	p.Ile93Val	missense_variant	4/14	ENST00000637790.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASAH1	ENST00000637790.2	c.277A>G	p.Ile93Val	missense_variant	4/14	1	NM_177924.5	P2

Frequencies

GnomAD3 genomes AF: 0.430 AC: 65269 AN: 151884 Hom.: 14930 Cov.: 32

Gnomad AFR AF: 0.276

Gnomad AMI AF: 0.577

Gnomad AMR AF: 0.528

Gnomad ASJ AF: 0.619

Gnomad EAS AF: 0.380

Gnomad SAS AF: 0.522

Gnomad FIN AF: 0.421

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.487

Gnomad OTH AF: 0.464

GnomAD3 exomes AF: 0.489 AC: 121672 AN: 248828 Hom.: 31316 AF XY: 0.492 AC XY: 66227 AN XY: 134672

Gnomad AFR exome AF: 0.270

Gnomad AMR exome AF: 0.656

Gnomad ASJ exome AF: 0.609

Gnomad EAS exome AF: 0.363

Gnomad SAS exome AF: 0.534

Gnomad FIN exome AF: 0.408

Gnomad NFE exome AF: 0.482

Gnomad OTH exome AF: 0.492

GnomAD4 exome AF: 0.480 AC: 676870 AN: 1410986 Hom.: 166960 Cov.: 30 AF XY: 0.483 AC XY: 339973 AN XY: 704054

Gnomad4 AFR exome AF: 0.261

Gnomad4 AMR exome AF: 0.640

Gnomad4 ASJ exome AF: 0.606

Gnomad4 EAS exome AF: 0.401

Gnomad4 SAS exome AF: 0.537

Gnomad4 FIN exome AF: 0.410

Gnomad4 NFE exome AF: 0.479

Gnomad4 OTH exome AF: 0.473

GnomAD4 genome AF: 0.430 AC: 65324 AN: 152000 Hom.: 14946 Cov.: 32 AF XY: 0.430 AC XY: 31976 AN XY: 74278

Gnomad4 AFR AF: 0.276

Gnomad4 AMR AF: 0.528

Gnomad4 ASJ AF: 0.619

Gnomad4 EAS AF: 0.380

Gnomad4 SAS AF: 0.524

Gnomad4 FIN AF: 0.421

Gnomad4 NFE AF: 0.487

Gnomad4 OTH AF: 0.461

Alfa AF: 0.491 Hom.: 45900

Bravo AF: 0.434

TwinsUK AF: 0.482 AC: 1786

ALSPAC AF: 0.490 AC: 1887

ESP6500AA AF: 0.285 AC: 1253

ESP6500EA AF: 0.492 AC: 4229

ExAC AF: 0.479 AC: 58171

Asia WGS AF: 0.419 AC: 1458 AN: 3478

EpiCase AF: 0.501

EpiControl AF: 0.505

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	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: 48% of total chromosomes in ExAC -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 06, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2018	This variant is associated with the following publications: (PMID: 23385296) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Farber lipogranulomatosis Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Spinal muscular atrophy-progressive myoclonic epilepsy syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.0010
Dann	Benign	0.30
DEOGEN2	Benign	0.24	T;T;T;.;T;T;T;T;T;T;T;.;.;T;T;T;T;T;T;T;.;.;.;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.013	N
MetaRNN	Benign	0.0000039	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.015	N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.32	T
Polyphen		0.0	B;B;B;B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.015, 0.0090, 0.018
MPC		0.0035
ClinPred		0.022	T
GERP RS		-11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.016
gMVP		0.72

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

Publications

LitVar

Other links and lift over

dbSNP: rs1049874; hg19: chr8-17927327; COSMIC: COSV50501249; COSMIC: COSV50501249;