chr8-18061425-A-G

Variant names:

• chr8-18061425-A-G
• rs10103355
• NM_177924.5:c.737T>C

Variant summary

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

The NM_177924.5(ASAH1):​c.737T>C​(p.Val246Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.966 in 1,612,938 control chromosomes in the GnomAD database, including 758,609 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (60692 hom., cov: 33)
  • Exomes 𝑓: 0.98 (697917 hom.)
• Consequence: ASAH1 NM_177924.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 2.96

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

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a chain Acid ceramidase subunit beta (size 252) in uniprot entity ASAH1_HUMAN there are 37 pathogenic changes around while only 6 benign (86%) in NM_177924.5
• BP4: Computational evidence support a benign effect (MetaRNN=5.797227E-7).
• BP6: Variant 8-18061425-A-G is Benign according to our data. Variant chr8-18061425-A-G is described in ClinVar as [Benign]. Clinvar id is 259283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-18061425-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.985 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASAH1	NM_177924.5	c.737T>C	p.Val246Ala	missense_variant	Exon 10 of 14	ENST00000637790.2	NP_808592.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASAH1	ENST00000637790.2	c.737T>C	p.Val246Ala	missense_variant	Exon 10 of 14	1	NM_177924.5	ENSP00000490272.1

Frequencies

GnomAD3 genomes AF: 0.878 AC: 133534 AN: 152090 Hom.: 60671 Cov.: 33

Gnomad AFR AF: 0.620

Gnomad AMI AF: 0.999

Gnomad AMR AF: 0.946

Gnomad ASJ AF: 0.996

Gnomad EAS AF: 0.876

Gnomad SAS AF: 0.963

Gnomad FIN AF: 0.964

Gnomad MID AF: 0.956

Gnomad NFE AF: 0.991

Gnomad OTH AF: 0.913

GnomAD2 exomes AF: 0.948 AC: 238477 AN: 251432 AF XY: 0.955

Gnomad AFR exome AF: 0.609

Gnomad AMR exome AF: 0.972

Gnomad ASJ exome AF: 0.994

Gnomad EAS exome AF: 0.869

Gnomad FIN exome AF: 0.967

Gnomad NFE exome AF: 0.991

Gnomad OTH exome AF: 0.963

GnomAD4 exome AF: 0.976 AC: 1425052 AN: 1460730 Hom.: 697917 Cov.: 46 AF XY: 0.976 AC XY: 709507 AN XY: 726806

Gnomad4 AFR exome AF: 0.609 AC: 20345 AN: 33434

Gnomad4 AMR exome AF: 0.969 AC: 43331 AN: 44722

Gnomad4 ASJ exome AF: 0.994 AC: 25972 AN: 26126

Gnomad4 EAS exome AF: 0.898 AC: 35627 AN: 39686

Gnomad4 SAS exome AF: 0.961 AC: 82901 AN: 86238

Gnomad4 FIN exome AF: 0.968 AC: 51726 AN: 53418

Gnomad4 NFE exome AF: 0.992 AC: 1102174 AN: 1110988

Gnomad4 Remaining exome AF: 0.953 AC: 57494 AN: 60350

GnomAD4 genome AF: 0.878 AC: 133604 AN: 152208 Hom.: 60692 Cov.: 33 AF XY: 0.879 AC XY: 65396 AN XY: 74432

Gnomad4 AFR AF: 0.620 AC: 0.619593 AN: 0.619593

Gnomad4 AMR AF: 0.947 AC: 0.946653 AN: 0.946653

Gnomad4 ASJ AF: 0.996 AC: 0.995968 AN: 0.995968

Gnomad4 EAS AF: 0.876 AC: 0.876255 AN: 0.876255

Gnomad4 SAS AF: 0.963 AC: 0.963293 AN: 0.963293

Gnomad4 FIN AF: 0.964 AC: 0.963936 AN: 0.963936

Gnomad4 NFE AF: 0.991 AC: 0.991166 AN: 0.991166

Gnomad4 OTH AF: 0.914 AC: 0.914055 AN: 0.914055

Alfa AF: 0.959 Hom.: 213826

Bravo AF: 0.862

TwinsUK AF: 0.993 AC: 3683

ALSPAC AF: 0.992 AC: 3822

ESP6500AA AF: 0.624 AC: 2749

ESP6500EA AF: 0.991 AC: 8522

ExAC AF: 0.943 AC: 114493

Asia WGS AF: 0.902 AC: 3137 AN: 3478

EpiCase AF: 0.989

EpiControl AF: 0.990

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 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: 94% of total chromosomes in ExAC -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:4

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 22, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

Farber lipogranulomatosis Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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;C1834569:Spinal muscular atrophy-progressive myoclonic epilepsy syndrome Benign:1

Mar 30, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	20
DANN	Benign	0.84
DEOGEN2	Benign	0.39	T;T;T;.;T;T;T;T;T;T;T;.;.;.;.;T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.050	.;T;T;T;T;.;T;T;T;T;T;T;T;T;T;T
MetaRNN	Benign	5.8e-7	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-2.4	N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	2.8	.;N;N;N;.;.;.;.;.;.;.;.;.;.;N;.
REVEL	Benign	0.26
Sift	Benign	1.0	.;T;T;T;.;.;.;.;.;.;.;.;.;.;T;.
Sift4G	Benign	1.0	.;T;T;T;.;.;.;.;.;.;.;.;.;.;T;.
Polyphen		0.0	B;B;B;B;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.042, 0.032, 0.046
MPC		0.0028
ClinPred		0.0082	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.035
gMVP		0.59
Mutation Taster		=97/3	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

Publications

LitVar

Other links and lift over

dbSNP: rs10103355; hg19: chr8-17918934; COSMIC: COSV107253727; COSMIC: COSV107253727;