8-18064458-T-G

Variant names:

• chr8-18064458-T-G
• rs200455852
• NM_177924.5:c.456A>C

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 14P and 1B. PS3 PM2 PP5_Very_Strong BP4

The NM_177924.5(ASAH1):​c.456A>C​(p.Lys152Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000092 in 1,553,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/26 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001161424: Acid ceramidase enzyme activity was measured in this patient's and mother's fibroblasts. The patient has approximately 15% enzyme activity of controls and the mother has acid ceramidase activity of approximately 50% normal. DOI: 10.1016/j.nmd.2015.09.007" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. K152K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000098 (0 hom.)
• Consequence: ASAH1 NM_177924.5 missense, splice_region
• Scores: Splicing: ADA: 0.1912
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 U:1
• Conservation: PhyloP100: 1.30
• Publications: 12 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: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• spinal muscular atrophy-progressive myoclonic epilepsy syndrome

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

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001161424: Acid ceramidase enzyme activity was measured in this patient's and mother's fibroblasts. The patient has approximately 15% enzyme activity of controls and the mother has acid ceramidase activity of approximately 50% normal. DOI: 10.1016/j.nmd.2015.09.007; SCV000994982: RNA studies demonstrate in-frame skipping of exon 6 (PMID: 24164096); SCV004720033: Functional studies in cultured fibroblasts showed significantly reduced acid ceramidase enzymatic activity (Dyment et al. 2014. Pubmed ID: 24164096).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-18064458-T-G is Pathogenic according to our data. Variant chr8-18064458-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 180643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.18940812). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177924.5. 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.456A>C	p.Lys152Asn	missense splice_region	Exon 6 of 14	NP_808592.2	Q13510-1
	ASAH1	NM_004315.6		c.504A>C	p.Lys168Asn	missense splice_region	Exon 6 of 14	NP_004306.3
	ASAH1	NM_001127505.3		c.438A>C	p.Lys146Asn	missense splice_region	Exon 6 of 14	NP_001120977.1	Q13510-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASAH1	ENST00000637790.2	TSL:1 MANE Select	c.456A>C	p.Lys152Asn	missense splice_region	Exon 6 of 14	ENSP00000490272.1	Q13510-1
	ASAH1	ENST00000381733.9	TSL:1	c.504A>C	p.Lys168Asn	missense splice_region	Exon 6 of 14	ENSP00000371152.4	Q13510-2
	ASAH1	ENST00000314146.10	TSL:1	c.438A>C	p.Lys146Asn	missense splice_region	Exon 6 of 14	ENSP00000326970.10	Q13510-3

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000576 AC: 14 AN: 243106 AF XY: 0.0000304

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000470

Gnomad NFE exome AF: 0.0000734

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000978 AC: 137 AN: 1401324 Hom.: 0 Cov.: 28 AF XY: 0.0000900 AC XY: 63 AN XY: 699890

African (AFR) AF: 0.00 AC: 0 AN: 31866

American (AMR) AF: 0.000180 AC: 8 AN: 44350

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25592

East Asian (EAS) AF: 0.00 AC: 0 AN: 39186

South Asian (SAS) AF: 0.00 AC: 0 AN: 84456

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52878

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5634

European-Non Finnish (NFE) AF: 0.000114 AC: 121 AN: 1058978

Other (OTH) AF: 0.000137 AC: 8 AN: 58384

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152218 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74366

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.000131 AC: 2 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000774 Hom.: 0

Bravo AF: 0.0000453

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000741 AC: 9

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	1	-	Spinal muscular atrophy-progressive myoclonic epilepsy syndrome (3)
2	-	-	not provided (2)
1	-	-	ASAH1-related disorders (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.81	L
PhyloP100		1.3
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.24
Sift	Benign	0.42	T
Sift4G	Benign	0.68	T
Polyphen		0.0010	B
Vest4		0.21
MVP		0.82
MPC		0.0029
ClinPred		0.052	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.79
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.19
dbscSNV1_RF	Benign	0.41
SpliceAI score (max)		0.41		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.41		Position offset: -1

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

Other links and lift over

dbSNP: rs200455852; hg19: chr8-17921967;