chr8-18071302-C-T

Position:

chr8-18071302-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 linkuse as main transcript	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 linkuse as main transcript	c.214G>A	p.Val72Met	missense_variant, splice_region_variant	3/14	1	NM_177924.5	P2	Q13510-1

Frequencies

GnomAD3 genomes

AF:

0.430

AC:

65204

AN:

151720

Hom.:

14920

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.486

AC XY:

339797

AN XY:

698614

show subpopulations

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.:

AF XY:

0.431

AC XY:

31928

AN XY:

74156

show subpopulations

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

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2018	This variant is associated with the following publications: (PMID: 27026573) -
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	Athena Diagnostics	Apr 20, 2017	- -

Farber lipogranulomatosis

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
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. -

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

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

LIST_S2

Benign

0.044

.;T;T;T;T;.;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.;T;T

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

MutationAssessor

Benign

-0.41

N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

P;P;P;P;P

PrimateAI

Benign

0.26

PROVEAN

Benign

0.28

.;N;N;N;.;.;.;.;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.

REVEL

Benign

0.038

Sift

Benign

0.21

.;T;T;T;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.

Sift4G

Benign

0.10

.;T;T;T;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.

Polyphen

0.0010

B;B;B;B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.055, 0.032, 0.043, 0.068

MPC

0.0031

ClinPred

0.0036

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over