rs12948217

Variant names:

• chr17-3494408-C-A
• rs12948217
• NM_000049.4:c.693C>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000049.4(ASPA):​c.693C>A​(p.Tyr231*) 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:14 O:1
• Conservation: PhyloP100: 0.453
• Publications: 43 publications found

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]

SPATA22 Gene-Disease associations (from GenCC):

• infertility disorder

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 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 VariationId is 2609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPA	NM_000049.4	c.693C>A	p.Tyr231*	stop_gained	Exon 5 of 6	ENST00000263080.3	NP_000040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASPA	ENST00000263080.3	c.693C>A	p.Tyr231*	stop_gained	Exon 5 of 6	1	NM_000049.4	ENSP00000263080.2
ASPA	ENST00000456349.6	c.693C>A	p.Tyr231*	stop_gained	Exon 6 of 7	1		ENSP00000409976.2
SPATA22	ENST00000541913.5	c.-74+19004G>T		intron_variant	Intron 1 of 8	2		ENSP00000441920.1
SPATA22	ENST00000570318.1	c.-74+19203G>T		intron_variant	Intron 1 of 1	2		ENSP00000459147.1

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

GnomAD2 exomes AF: 0.0000557 AC: 14 AN: 251370 AF XY: 0.0000442

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33432

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00138 AC: 36 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1110508

Other (OTH) AF: 0.0000995 AC: 6 AN: 60330

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

African (AFR) AF: 0.00 AC: 0 AN: 41366

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67978

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0295 Hom.: 4130

ExAC AF: 0.0000576 AC: 7

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spongy degeneration of central nervous system Pathogenic:9 Other:1

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 07, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 17, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 22, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 29, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 20, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 04, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Pathogenic:2

Sep 08, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Jul 14, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Dec 13, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

ASPA-related disorder Pathogenic:1

Jul 08, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ASPA c.693C>A variant is predicted to result in premature protein termination (p.Tyr231*). This variant was reported in the compound heterozygous or homozygous states in individuals with Canavan disease, and is one of the most common causative variants in this gene in the Ashkenazi Jewish population (Kaul et al. 1994. PubMed ID: 8023850; Kaul et al. 1996. PubMed ID: 8659549; Zeng et al. 2002. PubMed ID: 12638939). This variant is reported in 0.14% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Nonsense variants in ASPA are expected to be pathogenic. This variant is interpreted as pathogenic. -

Canavan Disease, Familial Form Pathogenic:1

May 06, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.45
Vest4		0.95
GERP RS		3.5
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs12948217; hg19: chr17-3397702;