rs137853595

Positions:

• chr8-18075559-T-C
• chr8-18075559-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_177924.5(ASAH1):​c.107A>G​(p.Tyr36Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASAH1 NM_177924.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.25

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.906
• PP5: Variant 8-18075559-T-C is Pathogenic according to our data. Variant chr8-18075559-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 93.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASAH1	NM_177924.5	c.107A>G	p.Tyr36Cys	missense_variant	2/14	ENST00000637790.2	NP_808592.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASAH1	ENST00000637790.2	c.107A>G	p.Tyr36Cys	missense_variant	2/14	1	NM_177924.5	ENSP00000490272	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000688 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Farber lipogranulomatosis Pathogenic:2

Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Apr 16, 2018	This variant is interpreted as a Likely Pathogenic, for Farber lipogranulomatosis, Autosomal Recessive inheritance. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect (PMID:11241842). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2001	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;D;T;.;T;T;T;T;T;.;.;.;.;T;T;T;T;T;.;T;T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Pathogenic	2.9	M;M;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-7.2	.;D;D;D;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	.;D;D;D;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0030	.;D;D;D;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.
Polyphen		1.0	D;D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.88, 0.91, 0.85, 0.80
MutPred		0.76		Loss of phosphorylation at Y36 (P = 0.1059);Loss of phosphorylation at Y36 (P = 0.1059);Loss of phosphorylation at Y36 (P = 0.1059);.;.;Loss of phosphorylation at Y36 (P = 0.1059);Loss of phosphorylation at Y36 (P = 0.1059);Loss of phosphorylation at Y36 (P = 0.1059);Loss of phosphorylation at Y36 (P = 0.1059);Loss of phosphorylation at Y36 (P = 0.1059);Loss of phosphorylation at Y36 (P = 0.1059);.;.;Loss of phosphorylation at Y36 (P = 0.1059);Loss of phosphorylation at Y36 (P = 0.1059);Loss of phosphorylation at Y36 (P = 0.1059);Loss of phosphorylation at Y36 (P = 0.1059);Loss of phosphorylation at Y36 (P = 0.1059);.;.;.;
MVP		0.98
MPC		0.0066
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs137853595; hg19: chr8-17933068;