chr8-18084711-T-C

Position:

• chr8-18084711-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004315.6(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. 12/16 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 NM_004315.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.839

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:):

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASAH1	NM_004315.6	c.91A>G	p.Ile31Val	missense_variant	1/14		NP_004306.3
ASAH1	NM_001127505.3	c.91A>G	p.Ile31Val	missense_variant	1/14		NP_001120977.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASAH1	ENST00000381733.9	c.91A>G	p.Ile31Val	missense_variant	1/14	1		ENSP00000371152.4
ASAH1	ENST00000314146.10	c.91A>G	p.Ile31Val	missense_variant	1/14	1		ENSP00000326970.10
ASAH1	ENST00000637244.1	n.91A>G		non_coding_transcript_exon_variant	1/14	1		ENSP00000490188.1

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 199 AN: 152214 Hom.: 2 Cov.: 33

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

GnomAD3 exomes AF: 0.00272 AC: 680 AN: 249926 Hom.: 14 AF XY: 0.00259 AC XY: 350 AN XY: 135120

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 SAS exome AF: 0.00145

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.: 37 Cov.: 31 AF XY: 0.00144 AC XY: 1050 AN XY: 726946

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00720

Gnomad4 EAS exome AF: 0.0353

Gnomad4 SAS exome AF: 0.00163

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000148

Gnomad4 OTH exome AF: 0.00172

GnomAD4 genome AF: 0.00131 AC: 199 AN: 152332 Hom.: 2 Cov.: 33 AF XY: 0.00161 AC XY: 120 AN XY: 74488

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.0272

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00133 Hom.: 5

Bravo AF: 0.00172

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00289 AC: 351

Asia WGS AF: 0.00953 AC: 33 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 07, 2019

- -

ASAH1-related disorders Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 26, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	3.3
DANN	Benign	0.65
DEOGEN2	Benign	0.0063	.;T;.;.;.;T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.74	T;T;T;T;T;T;T
MetaRNN	Benign	0.0036	T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.020	N;.;.;N;.;.;.
REVEL	Benign	0.058
Sift	Benign	0.42	T;.;.;T;.;.;.
Sift4G	Benign	0.63	T;.;.;T;.;.;.
Polyphen		0.0	B;.;.;.;.;.;.
Vest4		0.068
MVP		0.11
MPC		0.0035
ClinPred		0.0057	T
GERP RS		-3.6
gMVP		0.32

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3213606; hg19: chr8-17942220; COSMIC: COSV50501653; COSMIC: COSV50501653;