8-18061458-C-A

Variant names:

• chr8-18061458-C-A
• rs886062781
• NM_177924.5:c.704G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Moderate PP5_Moderate

The NM_177924.5(ASAH1):​c.704G>T​(p.Gly235Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,457,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G235D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ASAH1 NM_177924.5 missense, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.36
• Publications: 3 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-18061458-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 362375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 8-18061458-C-A is Pathogenic according to our data. Variant chr8-18061458-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3066142.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASAH1	NM_177924.5	MANE Select	c.704G>T	p.Gly235Val	missense splice_region	Exon 10 of 14	NP_808592.2
	ASAH1	NM_004315.6		c.752G>T	p.Gly251Val	missense splice_region	Exon 10 of 14	NP_004306.3
	ASAH1	NM_001127505.3		c.686G>T	p.Gly229Val	missense splice_region	Exon 10 of 14	NP_001120977.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASAH1	ENST00000637790.2	TSL:1 MANE Select	c.704G>T	p.Gly235Val	missense splice_region	Exon 10 of 14	ENSP00000490272.1
	ASAH1	ENST00000381733.9	TSL:1	c.752G>T	p.Gly251Val	missense splice_region	Exon 10 of 14	ENSP00000371152.4
	ASAH1	ENST00000314146.10	TSL:1	c.686G>T	p.Gly229Val	missense splice_region	Exon 10 of 14	ENSP00000326970.10

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1457858 Hom.: 0 Cov.: 34 AF XY: 0.00000276 AC XY: 2 AN XY: 725582

African (AFR) AF: 0.00 AC: 0 AN: 33438

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1108266

Other (OTH) AF: 0.00 AC: 0 AN: 60274

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Farber lipogranulomatosis Pathogenic:1

Apr 14, 2023

MVZ Medizinische Genetik Mainz

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG Criteria: PM3,PM5,PP3_MOD,PM2_SUP

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.4
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-8.3	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.99	D
Vest4		0.94
MutPred		0.88		Gain of sheet (P = 0.1945)
MVP		0.97
MPC		0.010
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.96
gMVP		0.92
Mutation Taster		=7/93	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.040		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: rs886062781; hg19: chr8-17918967;