8-18061724-G-T

Position:

• chr8-18061724-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_177924.5(ASAH1):​c.665C>A​(p.Thr222Lys) 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. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ASAH1 NM_177924.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• 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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 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, 0.969
• PP5: Variant 8-18061724-G-T is Pathogenic according to our data. Variant chr8-18061724-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 91.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASAH1	NM_177924.5	c.665C>A	p.Thr222Lys	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>A	p.Thr222Lys	missense_variant	9/14	1	NM_177924.5	ENSP00000490272.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1427166 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 706674

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Farber lipogranulomatosis Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 20, 1996

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D;D;D;.;T;T;T;T;T;T;T;.;.;.;T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	.;D;D;D;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Pathogenic	3.1	M;M;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-4.7	.;D;D;D;.;.;.;.;.;.;.;.;.;D;.
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0020	.;D;D;D;.;.;.;.;.;.;.;.;.;D;.
Sift4G	Benign	0.065	.;T;T;T;.;.;.;.;.;.;.;.;.;T;.
Polyphen		0.99	D;D;D;D;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.94, 0.95, 0.95, 0.95
MutPred		0.91		Gain of ubiquitination at T222 (P = 0.0258);Gain of ubiquitination at T222 (P = 0.0258);.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.96
MPC		0.0078
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.92
gMVP		0.98

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: rs137853593; hg19: chr8-17919233;