rs766257867

Positions:

• chr8-18062391-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_177924.5(ASAH1):​c.536C>T​(p.Thr179Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ASAH1 NM_177924.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 5.18

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 7 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, 0.842
• PP5: Variant 8-18062391-G-A is Pathogenic according to our data. Variant chr8-18062391-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 560956.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASAH1	NM_177924.5	c.536C>T	p.Thr179Ile	missense_variant	8/14	ENST00000637790.2	NP_808592.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASAH1	ENST00000637790.2	c.536C>T	p.Thr179Ile	missense_variant	8/14	1	NM_177924.5	ENSP00000490272.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251406 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135880

Gnomad AFR exome AF: 0.000123

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461848 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727218

Gnomad4 AFR exome AF: 0.0000299

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

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Spinal muscular atrophy-progressive myoclonic epilepsy syndrome Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	literature only	Medical Affairs, Dicerna Pharmaceuticals	Jun 18, 2019	It is our recommendation to update the status of variant c.536C>T from VUS to pathogenic due to recent publications discussing the pathogenicity of this variant. Multiple patients have been diagnosed with SMA-PME who carry the c.546C>T variant. In Sathe et al., 2014, DOI: 10.1016/j.ymgme.2013.12.226, the patient presented with SMA-PME according to Gene Reviews (https://www.ncbi.nlm.nih.gov/books/NBK488189/). Compound heterozygous variants, c.536C>T and c.125A>G, were identified in the patient using whole genome sequencing. Variant c.536C>T has been identified in an additional unrelated patients diagnosed with SMA-PME including a patient listed in Clinvar and identified at Baylor College of Medicine (SCV000807360.1) and 1 patient published in Cozma et al., 2017, DOI:10.1038/s41598-017-06604-2. Ceramide biomarker analysis in this patient (Cozma et al., 2017) along with 9 additional Farber disease patients and 2 SMA-PME patients demonstrated that C26:0 levels were significantly higher in Farber patients and SMA-PME patients compared to controls. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	Likely pathogenicity based on finding it in trans with another missense mutation in a 14-year-old female with progressive cognitive impairment, flaccid proximal limb weakness with childhood onset, hyperreflexia, seizure disorder, dystonia, myoclonus, mild cerebral atrophy. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D;D;D;.;T;T;T;T;T;T;T;.;.;.;T;T;T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.087	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Pathogenic	3.1	M;M;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.8	.;D;D;D;.;.;.;.;.;.;.;.;.;D;.;.;.
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0010	.;D;D;D;.;.;.;.;.;.;.;.;.;D;.;.;.
Sift4G	Uncertain	0.0070	.;D;D;D;.;.;.;.;.;.;.;.;.;D;.;.;.
Polyphen		1.0	D;D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.70, 0.70, 0.68, 0.69
MutPred		0.59		Loss of ubiquitination at K183 (P = 0.1016);Loss of ubiquitination at K183 (P = 0.1016);.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.96
MPC		0.011
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.93

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: rs766257867; hg19: chr8-17919900;