8-18084701-A-G

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_004315.6(ASAH1):c.101T>C(p.Phe34Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000367 in 1,613,738 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00038 ( 1 hom. )

Consequence

ASAH1
NM_004315.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.288

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 -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.036254436).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000379 (554/1461440) while in subpopulation MID AF= 0.00243 (14/5768). AF 95% confidence interval is 0.00147. There are 1 homozygotes in gnomad4_exome. There are 291 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
ASAH1	NM_004315.6 link	c.101T>C	p.Phe34Ser	missense_variant	Exon 1 of 14	NP_004306.3	Q13510-2Q53H01A8K0B6
ASAH1	NM_001127505.3 link	c.101T>C	p.Phe34Ser	missense_variant	Exon 1 of 14	NP_001120977.1	Q13510-3Q53H01A8K0B6
ASAH1-AS1	NR_125429.1 link	n.-167A>G		upstream_gene_variant
ASAH1-AS1	NR_125430.1 link	n.-167A>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
ASAH1	ENST00000381733.9 link	c.101T>C	p.Phe34Ser	missense_variant	Exon 1 of 14	1	ENSP00000371152.4	Q13510-2
ASAH1	ENST00000314146.10 link	c.101T>C	p.Phe34Ser	missense_variant	Exon 1 of 14	1	ENSP00000326970.10	Q13510-3
ASAH1	ENST00000637244.1 link	n.101T>C		non_coding_transcript_exon_variant	Exon 1 of 14	1	ENSP00000490188.1	A0A1B0GUP1

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000333

AC:

AN:

249594

Hom.:

AF XY:

0.000378

AC XY:

AN XY:

134970

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000395

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000569

Gnomad OTH exome

AF:

0.000817

GnomAD4 exome

AF:

0.000379

AC:

554

AN:

1461440

Hom.:

Cov.:

AF XY:

0.000400

AC XY:

291

AN XY:

726948

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000302

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000430

Gnomad4 OTH exome

AF:

0.000497

GnomAD4 genome

AF:

0.000256

AC:

AN:

152298

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000470

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000425

Hom.:

Bravo

AF:

0.000261

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000338

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

May 02, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.101T>C (p.F34S) alteration is located in exon 1 (coding exon 1) of the ASAH1 gene. This alteration results from a T to C substitution at nucleotide position 101, causing the phenylalanine (F) at amino acid position 34 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.48

CADD

Benign

3.3

DANN

Benign

0.86

DEOGEN2

Benign

0.0063

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

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.075

LIST_S2

Benign

0.63

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

M_CAP

Benign

0.011

MetaRNN

Benign

0.036

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

MetaSVM

Benign

-0.95

PrimateAI

Benign

0.28

PROVEAN

Benign

0.27

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

REVEL

Benign

0.17

Sift

Benign

0.24

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

Sift4G

Uncertain

0.036

D;.;.;D;.;.;.

Polyphen

0.0020

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

Vest4

0.11

MVP

0.10

MPC

0.0022

ClinPred

0.041

GERP RS

-4.5

gMVP

0.36

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over