rs779888892

Variant names:

• chr8-18075542-T-C
• rs779888892
• NM_177924.5:c.124A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3 PP5

The NM_177924.5(ASAH1):​c.124A>G​(p.Thr42Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000752 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T42M) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: ASAH1 NM_177924.5 missense, splice_region
• Scores: Splicing: ADA: 0.9991
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 3.61
• Publications: 13 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: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• spinal muscular atrophy-progressive myoclonic epilepsy syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_177924.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-18075541-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 35544.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 8-18075542-T-C is Pathogenic according to our data. Variant chr8-18075542-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 560955.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASAH1	NM_177924.5	MANE Select	c.124A>G	p.Thr42Ala	missense splice_region	Exon 2 of 14	NP_808592.2	Q13510-1
	ASAH1	NM_004315.6		c.172A>G	p.Thr58Ala	missense splice_region	Exon 2 of 14	NP_004306.3
	ASAH1	NM_001127505.3		c.172A>G	p.Thr58Ala	missense splice_region	Exon 2 of 14	NP_001120977.1	Q13510-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASAH1	ENST00000637790.2	TSL:1 MANE Select	c.124A>G	p.Thr42Ala	missense splice_region	Exon 2 of 14	ENSP00000490272.1	Q13510-1
	ASAH1	ENST00000381733.9	TSL:1	c.172A>G	p.Thr58Ala	missense splice_region	Exon 2 of 14	ENSP00000371152.4	Q13510-2
	ASAH1	ENST00000314146.10	TSL:1	c.172A>G	p.Thr58Ala	missense splice_region	Exon 2 of 14	ENSP00000326970.10	Q13510-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251460 AF XY: 0.0000221

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461836 Hom.: 0 Cov.: 30 AF XY: 0.00000963 AC XY: 7 AN XY: 727224

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86258

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: 0.00 AC: 0 AN: 1111982

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

Alfa AF: 0.000111 Hom.: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Spinal muscular atrophy-progressive myoclonic epilepsy syndrome (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	0.20	D
PhyloP100		3.6
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.32
Sift	Benign	0.33	T
Sift4G	Benign	0.56	T
Polyphen		0.20	B
Vest4		0.59
MutPred		0.24		Loss of phosphorylation at T42 (P = 0.0137)
MVP		0.89
MPC		0.0088
ClinPred		0.97	D
GERP RS		5.1
PromoterAI		-0.060	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.52
gMVP		0.69
Mutation Taster		=50/50

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
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

Other links and lift over

dbSNP: rs779888892; hg19: chr8-17933051;