8-18061724-G-C

Position:

• chr8-18061724-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_177924.5(ASAH1):​c.665C>G​(p.Thr222Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASAH1 NM_177924.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.45

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a chain Acid ceramidase subunit beta (size 252) in uniprot entity ASAH1_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_177924.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASAH1	NM_177924.5	c.665C>G	p.Thr222Arg	missense_variant	9/14	ENST00000637790.2	NP_808592.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASAH1	ENST00000637790.2	c.665C>G	p.Thr222Arg	missense_variant	9/14	1	NM_177924.5	ENSP00000490272.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000507 AC: 1 AN: 197164 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 105048

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000120

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000830 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D;D;D;.;T;T;T;T;T;T;T;.;.;.;T
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	.;D;D;D;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Pathogenic	3.1	M;M;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-4.8	.;D;D;D;.;.;.;.;.;.;.;.;.;D;.
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	.;D;D;D;.;.;.;.;.;.;.;.;.;D;.
Sift4G	Uncertain	0.0060	.;D;D;D;.;.;.;.;.;.;.;.;.;D;.
Polyphen		0.99	D;D;D;D;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.93, 0.93, 0.93
MutPred		0.88		Gain of methylation at T222 (P = 0.0253);Gain of methylation at T222 (P = 0.0253);.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.95
MPC		0.0092
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.93
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs137853593; hg19: chr8-17919233;