rs1071645

Variant names:

• chr8-18071302-C-T
• rs1071645
• NM_177924.5:c.214G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004315.6(ASAH1):​c.262G>A​(p.Val88Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.478 in 1,553,802 control chromosomes in the GnomAD database, including 182,271 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.43 (14935 hom., cov: 31)
  • Exomes 𝑓: 0.48 (167336 hom.)
• Consequence: ASAH1 NM_004315.6 missense, splice_region
• Scores: Splicing: ADA: 0.00001074
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.552
• Publications: 41 publications found

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 Gene-Disease associations (from GenCC):

• ASAH1-related sphingolipidosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Farber lipogranulomatosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• spinal muscular atrophy-progressive myoclonic epilepsy syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.661483E-6).
• BP6: Variant 8-18071302-C-T is Benign according to our data. Variant chr8-18071302-C-T is described in ClinVar as Benign. ClinVar VariationId is 259278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.519 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004315.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASAH1	NM_177924.5	MANE Select	c.214G>A	p.Val72Met	missense splice_region	Exon 3 of 14	NP_808592.2
	ASAH1	NM_004315.6		c.262G>A	p.Val88Met	missense splice_region	Exon 3 of 14	NP_004306.3
	ASAH1	NM_001127505.3		c.283G>A	p.Val95Met	missense splice_region	Exon 4 of 14	NP_001120977.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASAH1	ENST00000637790.2	TSL:1 MANE Select	c.214G>A	p.Val72Met	missense splice_region	Exon 3 of 14	ENSP00000490272.1
	ASAH1	ENST00000381733.9	TSL:1	c.262G>A	p.Val88Met	missense splice_region	Exon 3 of 14	ENSP00000371152.4
	ASAH1	ENST00000314146.10	TSL:1	c.283G>A	p.Val95Met	missense splice_region	Exon 4 of 14	ENSP00000326970.10

Frequencies

GnomAD3 genomes AF: 0.430 AC: 65204 AN: 151720 Hom.: 14920 Cov.: 31

Gnomad AFR AF: 0.276

Gnomad AMI AF: 0.577

Gnomad AMR AF: 0.528

Gnomad ASJ AF: 0.619

Gnomad EAS AF: 0.381

Gnomad SAS AF: 0.523

Gnomad FIN AF: 0.420

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.487

Gnomad OTH AF: 0.465

GnomAD2 exomes AF: 0.487 AC: 112543 AN: 230982 AF XY: 0.490

Gnomad AFR exome AF: 0.267

Gnomad AMR exome AF: 0.653

Gnomad ASJ exome AF: 0.608

Gnomad EAS exome AF: 0.361

Gnomad FIN exome AF: 0.409

Gnomad NFE exome AF: 0.480

Gnomad OTH exome AF: 0.494

GnomAD4 exome AF: 0.484 AC: 678020 AN: 1401964 Hom.: 167336 Cov.: 27 AF XY: 0.486 AC XY: 339797 AN XY: 698614

African (AFR) AF: 0.265 AC: 8608 AN: 32480

American (AMR) AF: 0.638 AC: 27572 AN: 43216

Ashkenazi Jewish (ASJ) AF: 0.609 AC: 15478 AN: 25430

East Asian (EAS) AF: 0.401 AC: 15721 AN: 39158

South Asian (SAS) AF: 0.537 AC: 44660 AN: 83134

European-Finnish (FIN) AF: 0.411 AC: 21385 AN: 51992

Middle Eastern (MID) AF: 0.486 AC: 2545 AN: 5242

European-Non Finnish (NFE) AF: 0.484 AC: 514326 AN: 1063098

Other (OTH) AF: 0.476 AC: 27725 AN: 58214

GnomAD4 genome AF: 0.430 AC: 65259 AN: 151838 Hom.: 14935 Cov.: 31 AF XY: 0.431 AC XY: 31928 AN XY: 74156

African (AFR) AF: 0.276 AC: 11435 AN: 41406

American (AMR) AF: 0.529 AC: 8067 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.619 AC: 2144 AN: 3464

East Asian (EAS) AF: 0.381 AC: 1965 AN: 5152

South Asian (SAS) AF: 0.524 AC: 2527 AN: 4820

European-Finnish (FIN) AF: 0.420 AC: 4406 AN: 10486

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.487 AC: 33089 AN: 67932

Other (OTH) AF: 0.461 AC: 974 AN: 2112

Alfa AF: 0.472 Hom.: 34114

Bravo AF: 0.434

TwinsUK AF: 0.483 AC: 1791

ALSPAC AF: 0.489 AC: 1883

ESP6500AA AF: 0.289 AC: 1275

ESP6500EA AF: 0.493 AC: 4243

ExAC AF: 0.463 AC: 56120

Asia WGS AF: 0.419 AC: 1455 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	not specified (4)
-	-	2	Farber lipogranulomatosis (2)
-	-	1	Spinal muscular atrophy-progressive myoclonic epilepsy syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.26
DANN	Benign	0.32
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.093	N
LIST_S2	Benign	0.044	T
MetaRNN	Benign	0.000043	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.41	N
PhyloP100		0.55
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.28	N
REVEL	Benign	0.038
Sift	Benign	0.21	T
Sift4G	Benign	0.10	T
Polyphen		0.0010	B
Vest4		0.055
MPC		0.0031
ClinPred		0.0036	T
GERP RS		-3.3
Varity_R		0.016
gMVP		0.67
Mutation Taster		=89/11	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000011
dbscSNV1_RF	Benign	0.050
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1071645; hg19: chr8-17928811; COSMIC: COSV50502085; COSMIC: COSV50502085;