8-18084695-C-T

Position:

• chr8-18084695-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004315.6(ASAH1):​c.107G>A​(p.Ser36Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0526 in 1,613,174 control chromosomes in the GnomAD database, including 2,862 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.075 (600 hom., cov: 33)
  • Exomes 𝑓: 0.050 (2262 hom.)
• Consequence: ASAH1 NM_004315.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.139

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017465055).
• BP6: Variant 8-18084695-C-T is Benign according to our data. Variant chr8-18084695-C-T is described in ClinVar as [Benign]. Clinvar id is 558960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-18084695-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.145 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASAH1	NM_004315.6	c.107G>A	p.Ser36Asn	missense_variant	1/14		NP_004306.3
ASAH1	NM_001127505.3	c.107G>A	p.Ser36Asn	missense_variant	1/14		NP_001120977.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASAH1	ENST00000381733.9	c.107G>A	p.Ser36Asn	missense_variant	1/14	1		ENSP00000371152.4
ASAH1	ENST00000314146.10	c.107G>A	p.Ser36Asn	missense_variant	1/14	1		ENSP00000326970.10
ASAH1	ENST00000637244.1	n.107G>A		non_coding_transcript_exon_variant	1/14	1		ENSP00000490188.1

Frequencies

GnomAD3 genomes AF: 0.0743 AC: 11282 AN: 151790 Hom.: 592 Cov.: 33

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.0378

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.0529

Gnomad SAS AF: 0.0616

Gnomad FIN AF: 0.0343

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0492

Gnomad OTH AF: 0.0583

GnomAD3 exomes AF: 0.0493 AC: 12266 AN: 248932 Hom.: 428 AF XY: 0.0481 AC XY: 6478 AN XY: 134620

Gnomad AFR exome AF: 0.144

Gnomad AMR exome AF: 0.0193

Gnomad ASJ exome AF: 0.0236

Gnomad EAS exome AF: 0.0508

Gnomad SAS exome AF: 0.0595

Gnomad FIN exome AF: 0.0323

Gnomad NFE exome AF: 0.0481

Gnomad OTH exome AF: 0.0394

GnomAD4 exome AF: 0.0504 AC: 73600 AN: 1461268 Hom.: 2262 Cov.: 31 AF XY: 0.0505 AC XY: 36716 AN XY: 726822

Gnomad4 AFR exome AF: 0.151

Gnomad4 AMR exome AF: 0.0211

Gnomad4 ASJ exome AF: 0.0240

Gnomad4 EAS exome AF: 0.0747

Gnomad4 SAS exome AF: 0.0594

Gnomad4 FIN exome AF: 0.0343

Gnomad4 NFE exome AF: 0.0484

Gnomad4 OTH exome AF: 0.0509

GnomAD4 genome AF: 0.0745 AC: 11322 AN: 151906 Hom.: 600 Cov.: 33 AF XY: 0.0729 AC XY: 5413 AN XY: 74272

Gnomad4 AFR AF: 0.148

Gnomad4 AMR AF: 0.0377

Gnomad4 ASJ AF: 0.0248

Gnomad4 EAS AF: 0.0526

Gnomad4 SAS AF: 0.0617

Gnomad4 FIN AF: 0.0343

Gnomad4 NFE AF: 0.0492

Gnomad4 OTH AF: 0.0572

Alfa AF: 0.0509 Hom.: 446

Bravo AF: 0.0770

TwinsUK AF: 0.0415 AC: 154

ALSPAC AF: 0.0446 AC: 172

ESP6500AA AF: 0.145 AC: 640

ESP6500EA AF: 0.0484 AC: 416

ExAC AF: 0.0538 AC: 6535

Asia WGS AF: 0.0550 AC: 192 AN: 3478

EpiCase AF: 0.0430

EpiControl AF: 0.0415

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2018	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 26, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	6.1
DANN	Benign	0.87
DEOGEN2	Benign	0.018	.;T;.;.;.;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.74	T;T;T;T;T;T;T
MetaRNN	Benign	0.0017	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.97	N;.;.;N;.;.;.
REVEL	Benign	0.099
Sift	Benign	0.45	T;.;.;T;.;.;.
Sift4G	Benign	0.46	T;.;.;T;.;.;.
Polyphen		0.0070	B;.;.;.;.;.;.
Vest4		0.040
MPC		0.0033
ClinPred		0.0055	T
GERP RS		0.22
gMVP		0.30

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs13263632; hg19: chr8-17942204;