rs12948217

Positions:

• chr17-3494408-C-A
• chr17-3494408-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000049.4(ASPA):​c.693C>A​(p.Tyr231Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000416 in 1,612,170 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y231Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: ASPA NM_000049.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 0.453

Genes affected

ASPA (HGNC:756): (aspartoacylase) This gene encodes an enzyme that catalyzes the conversion of N-acetyl_L-aspartic acid (NAA) to aspartate and acetate. NAA is abundant in the brain where hydrolysis by aspartoacylase is thought to help maintain white matter. This protein is an NAA scavenger in other tissues. Mutations in this gene cause Canavan disease. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2008]

SPATA22 (HGNC:30705): (spermatogenesis associated 22) Predicted to be involved in regulation of meiotic cell cycle. Predicted to act upstream of or within several processes, including fertilization; gamete generation; and meiosis I cell cycle process. Predicted to be located in chromosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-3494408-C-A is Pathogenic according to our data. Variant chr17-3494408-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 2609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-3494408-C-A is described in Lovd as [Pathogenic]. Variant chr17-3494408-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASPA	NM_000049.4	c.693C>A	p.Tyr231Ter	stop_gained	5/6	ENST00000263080.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPA	ENST00000263080.3	c.693C>A	p.Tyr231Ter	stop_gained	5/6	1	NM_000049.4	P1
ASPA	ENST00000456349.6	c.693C>A	p.Tyr231Ter	stop_gained	6/7	1		P1
SPATA22	ENST00000541913.5	c.-74+19004G>T		intron_variant		2
SPATA22	ENST00000570318.1	c.-74+19203G>T		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151980 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000557 AC: 14 AN: 251370 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135864

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000438 AC: 64 AN: 1460190 Hom.: 0 Cov.: 33 AF XY: 0.0000330 AC XY: 24 AN XY: 726552

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00138

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.0000995

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151980 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74214

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00208 Hom.: 3590

ExAC AF: 0.0000576 AC: 7

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spongy degeneration of central nervous system Pathogenic:8 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 04, 2019	NM_000049.2(ASPA):c.693C>A(Y231*) is classified as pathogenic in the context of Canavan disease. Sources cited for classification include the following: PMID 8023850. Classification of NM_000049.2(ASPA):c.693C>A(Y231*) is based on the following criteria: The variant causes a premature termination codon that is not expected to be targeted by nonsense-mediated mRNA decay; however, literature evidence strongly supports pathogenicity. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 20, 2014	The p.Tyr231X variant in ASPA has been reported in numerous individuals with Canavan disease (Kaul 1994) and is one of the most common disease-causing ASPA variants in the Ashkenazi Jewish population. It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 231 which is predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic for Canavan disease in an autosomal recessive manner. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 14, 2023	This sequence change creates a premature translational stop signal (p.Tyr231*) in the ASPA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ASPA are known to be pathogenic (PMID: 12638939). This variant is present in population databases (rs12948217, gnomAD 0.1%). This premature translational stop signal has been observed in individuals with Canavan disease (PMID: 8023850, 8659549, 10909858). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 8023850, 8659549, 10909858). ClinVar contains an entry for this variant (Variation ID: 2609). For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The ASPA c.693C>A (p.Tyr231Ter) variant is a stop-gained variant and is predicted to terminate the protein prematurely. It has been reported in two studies and is found in a total of 13 individuals with Canavan disease including one in a homozygous state and 12 in a compound heterozygous state (Kaul et al. 1994; Kaul et al. 1996). All of the individuals except one were of Ashkenazi Jewish descent. Control data are unavailable for this variant, which is reported at a frequency of 0.00011 in the European (non-Finnish) population of the Exome Aggregation Consortium. Kaul et al. (1994) demonstrated a complete loss of ASPA activity when the p.Tyr231Ter variant was expressed in COS-1 cells. Based on the collective evidence, the p.Tyr231Ter variant is classified as pathogenic for Canavan disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 29, 2024	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 14, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 08, 2022	Expression studies found that this variant causes complete loss of enzyme activity (Kaul et al., 1994); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 83 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 21228398, 25525159, 27535533, 25668701, 8023850) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2023

The c.693C>A (p.Y231*) alteration, located in exon 5 (coding exon 5) of the ASPA gene, consists of a C to A substitution at nucleotide position 693. This changes the amino acid from a tyrosine (Y) to a stop codon at amino acid position 231. This alteration occurs at the 3' terminus of the ASPA gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 26% of the protein. However, premature stop codons are typically deleterious in nature, a significant portion of the protein is affected, and the impacted region is critical for protein function (Ambry internal data). Based on data from gnomAD, the A allele has an overall frequency of 0.005% (15/282702) total alleles studied. The highest observed frequency was 0.135% (14/10368) of Ashkenazi Jewish alleles. This alteration was detected in the homozygous state, and in conjunction with another alteration in ASPA, in multiple individuals with Canavan Disease (Kaul, 1994; Yaron, 2005; Nguyen, 2015). In an in vitro assay testing ASPA function, this variant was reported as not expressing any measurable activity (Kaul, 1994). Based on the available evidence, this alteration is classified as pathogenic. -

Canavan Disease, Familial Form Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 06, 2016

Variant summary: The ASPA c.693C>A variant is a nonsense mutation resulting in a premature termination codon. It is predicted to cause a truncated or absent ASPA protein, which is a commonly known mechanism for disease. Mutation taster predicts damaging outcome for this variant. This variant is found in 7/121216 control chromosomes at a frequency of 0.0000577, which does not exceed maximal expected frequency of a pathogenic allele (0.0079057). It was reported in several Canavan Disease patients in either homozygosity or in compound heterozygosity with pathogenic ASPA alleles indicating pathogenicity. A functional study demonstrated the variant to result in complete loss of ASPA activity, further supporting a disease causing impact In addition, clinical diagnostic laboratories and reputable databases classify variant as Pathogenic. Moreover, the variant is known to account for 14.8% of the disease alleles in Ashkenazi Jewish patients. Taken together, this variant was classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Benign	0.18
Eigen_PC	Benign	0.030
FATHMM_MKL	Uncertain	0.81	D
MutationTaster	Benign	1.0	D;D;D
Vest4		0.95
GERP RS		3.5

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: rs12948217; hg19: chr17-3397702;