rs147896487

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000381733.9(ASAH1):c.35G>C(p.Arg12Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,613,634 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0015 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 4 hom. )

Consequence

ASAH1
ENST00000381733.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:3

Conservation

PhyloP100: -1.51

Publications

8 publications found

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 was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0040474534).

BP6

Variant 8-18084767-C-G is Benign according to our data. Variant chr8-18084767-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 433108.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00147 (224/152316) while in subpopulation NFE AF = 0.00222 (151/68022). AF 95% confidence interval is 0.00193. There are 3 homozygotes in GnomAd4. There are 118 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
ASAH1	NM_004315.6 link	c.35G>C	p.Arg12Pro	missense_variant	Exon 1 of 14	NP_004306.3	Q13510-2Q53H01A8K0B6
ASAH1	NM_001127505.3 link	c.35G>C	p.Arg12Pro	missense_variant	Exon 1 of 14	NP_001120977.1	Q13510-3Q53H01A8K0B6
ASAH1-AS1	NR_125429.1 link	n.-101C>G		upstream_gene_variant
ASAH1-AS1	NR_125430.1 link	n.-101C>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
ASAH1	ENST00000381733.9 link	c.35G>C	p.Arg12Pro	missense_variant	Exon 1 of 14	1	ENSP00000371152.4	Q13510-2
ASAH1	ENST00000314146.10 link	c.35G>C	p.Arg12Pro	missense_variant	Exon 1 of 14	1	ENSP00000326970.10	Q13510-3
ASAH1	ENST00000637244.1 link	n.35G>C		non_coding_transcript_exon_variant	Exon 1 of 14	1	ENSP00000490188.1	A0A1B0GUP1

Frequencies

GnomAD3 genomes

AF:

0.00147

AC:

224

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00537

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00222

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00133

AC:

333

AN:

249918

AF XY:

0.00133

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.000598

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00464

Gnomad NFE exome

AF:

0.00186

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

AF:

0.00118

AC:

1721

AN:

1461318

Hom.:

Cov.:

AF XY:

0.00127

AC XY:

922

AN XY:

726896

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33468

American (AMR)

AF:

0.000201

AC:

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.000728

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.000209

AC:

AN:

86050

European-Finnish (FIN)

AF:

0.00468

AC:

250

AN:

53392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00123

AC:

1372

AN:

1111806

Other (OTH)

AF:

0.000795

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

107

214

320

427

534

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00147

AC:

224

AN:

152316

Hom.:

Cov.:

AF XY:

0.00158

AC XY:

118

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.000216

AC:

AN:

41574

American (AMR)

AF:

0.0000653

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00537

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00222

AC:

151

AN:

68022

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00170

Hom.:

Bravo

AF:

0.000752

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.00142

AC:

172

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00142

EpiControl

AF:

0.00143

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

May 04, 2022

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 17, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ASAH1 c.-709G>C is located in the untranscribed region upstream of the ASAH1 gene region. The variant allele was found at a frequency of 0.0012 in 1613634 control chromosomes in the gnomAD database, including 7 homozygotes. The observed variant frequency is approximately 1.08-fold of the estimated maximal expected allele frequency for a pathogenic variant in ASAH1 causing Farber lipogranulomatosis phenotype (0.0011). c.-709G>C (also reported as c.35G>C) has been reported in the literature in at least one individual affected with clinical features of Farber lipogranulomatosis who carried 2 additional ASAH1 variants, a frameshift and missense variant, classified by authors as pathogenic and VUS, respectively, without phase reported (e.g. Axente_2021). The variant was also reported in individuals affected with Rolanidic epilepsy, without evidence of causality (e.g. Bobbili_2018). These reports do not provide unequivocal conclusions about association of the variant with Farber lipogranulomatosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34377212, 29358611). ClinVar contains an entry for this variant (Variation ID: 433108). Based on the evidence outlined above, the variant was classified as likely benign. -

Self-limited epilepsy with centrotemporal spikes

Pathogenic:1

Jan 01, 2017

Bioinformatics Core, Luxembourg Center for Systems Biomedicine

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:case-control

CAADphred>15 -

ASAH1-related sphingolipidosis

Uncertain:1

Oct 31, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Benign:1

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ASAH1: BP4, BS2; ASAH1-AS1: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.47

CADD

Benign

1.2

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.0063

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

Eigen

Benign

-0.96

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.80

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

M_CAP

Benign

0.019

MetaRNN

Benign

0.0040

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

MetaSVM

Benign

-0.93

PhyloP100

-1.5

PrimateAI

Benign

0.24

PROVEAN

Benign

0.060

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

REVEL

Benign

0.086

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

0.82

P;.;.;.;.;.;.

Vest4

0.35

MVP

0.42

MPC

0.0056

ClinPred

0.12

GERP RS

-2.1

PromoterAI

0.013

Neutral

(source)

gMVP

0.53

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over