Genetic Variant ENST00000381733.9:c.91A>G (chr8-18084711-T-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The ENST00000381733.9(ASAH1):c.91A>G(p.Ile31Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,613,758 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0013 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 37 hom. )

Consequence

ASAH1
ENST00000381733.9 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: -0.839

Publications

6 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036205351).

BP6

Variant 8-18084711-T-C is Benign according to our data. Variant chr8-18084711-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1215682.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00131 (199/152332) while in subpopulation EAS AF = 0.0272 (141/5180). AF 95% confidence interval is 0.0236. There are 2 homozygotes in GnomAd4. There are 120 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000381733.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ASAH1	NM_004315.6	c.91A>G	p.Ile31Val	missense	Exon 1 of 14	NP_004306.3
ASAH1	NM_001127505.3	c.91A>G	p.Ile31Val	missense	Exon 1 of 14	NP_001120977.1	Q13510-3
ASAH1-AS1	NR_125429.1	n.-157T>C		upstream_gene	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ASAH1	ENST00000381733.9	TSL:1	c.91A>G	p.Ile31Val	missense	Exon 1 of 14	ENSP00000371152.4	Q13510-2
ASAH1	ENST00000314146.10	TSL:1	c.91A>G	p.Ile31Val	missense	Exon 1 of 14	ENSP00000326970.10	Q13510-3
ASAH1	ENST00000637244.1	TSL:1	n.91A>G		non_coding_transcript_exon	Exon 1 of 14	ENSP00000490188.1	A0A1B0GUP1

Frequencies

GnomAD3 genomes

AF:

0.00131

AC:

199

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.0272

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00272

AC:

680

AN:

249926

AF XY:

0.00259

show subpopulations

Gnomad AFR exome

AF:

0.000743

Gnomad AMR exome

AF:

0.0000870

Gnomad ASJ exome

AF:

0.00847

Gnomad EAS exome

AF:

0.0275

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000213

Gnomad OTH exome

AF:

0.000981

GnomAD4 exome

AF:

0.00138

AC:

2021

AN:

1461426

Hom.:

Cov.:

AF XY:

0.00144

AC XY:

1050

AN XY:

726946

show subpopulations

African (AFR)

AF:

0.000418

AC:

AN:

33472

American (AMR)

AF:

0.0000895

AC:

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.00720

AC:

188

AN:

26116

East Asian (EAS)

AF:

0.0353

AC:

1403

AN:

39692

South Asian (SAS)

AF:

0.00163

AC:

140

AN:

86086

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000148

AC:

165

AN:

1111840

Other (OTH)

AF:

0.00172

AC:

104

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

118

235

353

470

588

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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:

0.00131

AC:

199

AN:

152332

Hom.:

Cov.:

AF XY:

0.00161

AC XY:

120

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.000481

AC:

AN:

41576

American (AMR)

AF:

0.00

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3472

East Asian (EAS)

AF:

0.0272

AC:

141

AN:

5180

South Asian (SAS)

AF:

0.00311

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68020

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00115

Hom.:

Bravo

AF:

0.00172

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00289

AC:

351

Asia WGS

AF:

0.00953

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

ASAH1-related disorders (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.55

CADD

Benign

3.3

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.0063

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.079

LIST_S2

Benign

0.74

MetaRNN

Benign

0.0036

MetaSVM

Benign

-0.98

PhyloP100

-0.84

PrimateAI

Benign

0.28

PROVEAN

Benign

0.020

REVEL

Benign

0.058

Sift

Benign

0.42

Sift4G

Benign

0.63

Polyphen

0.0

Vest4

0.068

MVP

0.11

MPC

0.0035

ClinPred

0.0057

GERP RS

-3.6

PromoterAI

-0.050

Neutral

(source)

gMVP

0.32

Mutation Taster

=99/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over