dbSNP rs200771465: ASAH1:p.Arg16Leu (chr8-18084755-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_004315.6(ASAH1):c.47G>T(p.Arg16Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R16P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

ASAH1
NM_004315.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.777

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:

ASAH1-AS1 (HGNC:55603): (ASAH1 antisense RNA 1)

ASAH1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.023436248).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
ASAH1	NM_004315.6 link	c.47G>T	p.Arg16Leu	missense_variant	Exon 1 of 14	NP_004306.3	Q13510-2Q53H01A8K0B6
ASAH1	NM_001127505.3 link	c.47G>T	p.Arg16Leu	missense_variant	Exon 1 of 14	NP_001120977.1	Q13510-3Q53H01A8K0B6
ASAH1-AS1	NR_125429.1 link	n.-113C>A		upstream_gene_variant
ASAH1-AS1	NR_125430.1 link	n.-113C>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
ASAH1	ENST00000381733.9 link	c.47G>T	p.Arg16Leu	missense_variant	Exon 1 of 14	1	ENSP00000371152.4	Q13510-2
ASAH1	ENST00000314146.10 link	c.47G>T	p.Arg16Leu	missense_variant	Exon 1 of 14	1	ENSP00000326970.10	Q13510-3
ASAH1	ENST00000637244.1 link	n.47G>T		non_coding_transcript_exon_variant	Exon 1 of 14	1	ENSP00000490188.1	A0A1B0GUP1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000280

AC:

AN:

249958

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135122

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461386

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726916

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000247

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.61

CADD

Benign

1.2

DANN

Benign

0.57

DEOGEN2

Benign

0.0062

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

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.71

T;T;T;T;T;T;T

M_CAP

Benign

0.0094

MetaRNN

Benign

0.023

T;T;T;T;T;T;T

MetaSVM

Benign

-0.82

PrimateAI

Benign

0.20

PROVEAN

Benign

0.080

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

REVEL

Benign

0.093

Sift

Benign

0.74

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

Sift4G

Benign

0.97

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

Polyphen

0.0

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

Vest4

0.10

MutPred

0.30

Loss of phosphorylation at S18 (P = 0.0531);Loss of phosphorylation at S18 (P = 0.0531);Loss of phosphorylation at S18 (P = 0.0531);Loss of phosphorylation at S18 (P = 0.0531);Loss of phosphorylation at S18 (P = 0.0531);Loss of phosphorylation at S18 (P = 0.0531);Loss of phosphorylation at S18 (P = 0.0531);

MVP

0.24

MPC

0.0027

ClinPred

0.046

GERP RS

-6.5

gMVP

0.53

Splicing

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over