rs1071645

chr8-18071302-C-T

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.214G>A(p.Val72Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.478 in 1,553,802 control chromosomes in the GnomAD database, including 182,271 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14935 hom., cov: 31)
  • Exomes 𝑓: 0.48 (167336 hom.)
• Consequence: ASAH1 NM_177924.5 missense, splice_region
• Scores: Splicing: ADA: 0.00001074
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.552

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=6.661483E-6).
• BP6: Variant 8-18071302-C-T is Benign according to our data. Variant chr8-18071302-C-T is described in ClinVar as [Benign]. Clinvar id is 259278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-18071302-C-T is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
ASAH1	NM_177924.5	c.214G>A	p.Val72Met	missense_variant, splice_region_variant	3/14	ENST00000637790.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASAH1	ENST00000637790.2	c.214G>A	p.Val72Met	missense_variant, splice_region_variant	3/14	1	NM_177924.5	P2

Frequencies

GnomAD3 genomes AF: 0.430 AC: 65204 AN: 151720 Hom.: 14920 Cov.: 31

Gnomad AFR AF: 0.276

Gnomad AMI AF: 0.577

Gnomad AMR AF: 0.528

Gnomad ASJ AF: 0.619

Gnomad EAS AF: 0.381

Gnomad SAS AF: 0.523

Gnomad FIN AF: 0.420

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.487

Gnomad OTH AF: 0.465

GnomAD3 exomes AF: 0.487 AC: 112543 AN: 230982 Hom.: 28638 AF XY: 0.490 AC XY: 60934 AN XY: 124416

Gnomad AFR exome AF: 0.267

Gnomad AMR exome AF: 0.653

Gnomad ASJ exome AF: 0.608

Gnomad EAS exome AF: 0.361

Gnomad SAS exome AF: 0.532

Gnomad FIN exome AF: 0.409

Gnomad NFE exome AF: 0.480

Gnomad OTH exome AF: 0.494

GnomAD4 exome AF: 0.484 AC: 678020 AN: 1401964 Hom.: 167336 Cov.: 27 AF XY: 0.486 AC XY: 339797 AN XY: 698614

Gnomad4 AFR exome AF: 0.265

Gnomad4 AMR exome AF: 0.638

Gnomad4 ASJ exome AF: 0.609

Gnomad4 EAS exome AF: 0.401

Gnomad4 SAS exome AF: 0.537

Gnomad4 FIN exome AF: 0.411

Gnomad4 NFE exome AF: 0.484

Gnomad4 OTH exome AF: 0.476

GnomAD4 genome AF: 0.430 AC: 65259 AN: 151838 Hom.: 14935 Cov.: 31 AF XY: 0.431 AC XY: 31928 AN XY: 74156

Gnomad4 AFR AF: 0.276

Gnomad4 AMR AF: 0.529

Gnomad4 ASJ AF: 0.619

Gnomad4 EAS AF: 0.381

Gnomad4 SAS AF: 0.524

Gnomad4 FIN AF: 0.420

Gnomad4 NFE AF: 0.487

Gnomad4 OTH AF: 0.461

Alfa AF: 0.481 Hom.: 23649

Bravo AF: 0.434

TwinsUK AF: 0.483 AC: 1791

ALSPAC AF: 0.489 AC: 1883

ESP6500AA AF: 0.289 AC: 1275

ESP6500EA AF: 0.493 AC: 4243

ExAC AF: 0.463 AC: 56120

Asia WGS AF: 0.419 AC: 1455 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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: 54% 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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:4

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2018	This variant is associated with the following publications: (PMID: 27026573) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -

Farber lipogranulomatosis Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	0.064
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	0.26
Dann	Benign	0.32
DEOGEN2	Benign	0.22	T;T;T;.;T;T;T;T;T;T;T;.;.;.;.;T;T;T;T;T;T;T;.;.;.;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.093	N
MetaRNN	Benign	0.000043	T;T;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	-0.95	T
MutationAssessor	Benign	-0.41	N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.26	T
Polyphen		0.0010	B;B;B;B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.055, 0.032, 0.043, 0.068
MPC		0.0031
ClinPred		0.0036	T
GERP RS		-3.3
Varity_R		0.016
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000011
dbscSNV1_RF	Benign	0.050
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: rs1071645; hg19: chr8-17928811; COSMIC: COSV50502085; COSMIC: COSV50502085;