rs147896487

chr8-18084767-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (4 hom.)
• Consequence: ASAH1 ENST00000381733.9 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:2
• Conservation: PhyloP100: -1.51

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

ACMG classification

Verdict is Benign. Variant got -16 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 [Likely_benign]. Clinvar id is 433108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-18084767-C-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASAH1	NM_004315.6	c.35G>C	p.Arg12Pro	missense_variant	1/14
ASAH1	NM_001127505.3	c.35G>C	p.Arg12Pro	missense_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASAH1-AS1	ENST00000665050.1	n.382C>G		non_coding_transcript_exon_variant	1/3

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 224 AN: 152198 Hom.: 3 Cov.: 32

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

GnomAD3 exomes AF: 0.00133 AC: 333 AN: 249918 Hom.: 1 AF XY: 0.00133 AC XY: 179 AN XY: 135092

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 SAS exome AF: 0.000198

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.: 4 Cov.: 31 AF XY: 0.00127 AC XY: 922 AN XY: 726896

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.000728

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00468

Gnomad4 NFE exome AF: 0.00123

Gnomad4 OTH exome AF: 0.000795

GnomAD4 genome AF: 0.00147 AC: 224 AN: 152316 Hom.: 3 Cov.: 32 AF XY: 0.00158 AC XY: 118 AN XY: 74474

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00537

Gnomad4 NFE AF: 0.00222

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00170 Hom.: 2

Bravo AF: 0.000752

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00142 AC: 172

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00142

EpiControl AF: 0.00143

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Childhood epilepsy with centrotemporal spikes Pathogenic:1

Pathogenic, no assertion criteria provided

case-control

Bioinformatics Core, Luxembourg Center for Systems Biomedicine

Jan 01, 2017

CAADphred>15 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2023

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	1.2
Dann	Benign	0.97
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.80	T;T;T;T;T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0040	T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.24	T
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	T
GERP RS		-2.1
gMVP		0.53

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs147896487; hg19: chr8-17942276;