rs28940574

chr17-3499060-C-Achr17-3499060-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_000049.4(ASPA):c.914C>A(p.Ala305Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000302 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: ASPA NM_000049.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:17 O:1
• Conservation: PhyloP100: 2.83

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 12 ACMG points.

• PM1: In a strand (size 11) in uniprot entity ACY2_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000049.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-3499060-C-A is Pathogenic according to our data. Variant chr17-3499060-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 2607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-3499060-C-A is described in Lovd as [Pathogenic]. Variant chr17-3499060-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASPA	NM_000049.4	c.914C>A	p.Ala305Glu	missense_variant	6/6	ENST00000263080.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPA	ENST00000263080.3	c.914C>A	p.Ala305Glu	missense_variant	6/6	1	NM_000049.4	P1
ASPA	ENST00000456349.6	c.914C>A	p.Ala305Glu	missense_variant	7/7	1		P1
SPATA22	ENST00000541913.5	c.-74+14352G>T		intron_variant		2
SPATA22	ENST00000570318.1	c.-74+14551G>T		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152094 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000207 AC: 52 AN: 251096 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135720

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000116

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: 0.000388

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000317 AC: 464 AN: 1461776 Hom.: 0 Cov.: 31 AF XY: 0.000323 AC XY: 235 AN XY: 727190

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.0000895

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: 0.000403

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74426

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000398 Hom.: 0

Bravo AF: 0.000144

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000222 AC: 27

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spongy degeneration of central nervous system Pathogenic:13 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 1995	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 07, 2021	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Feb 22, 2019	This established pathogenic variant has been previously reported as a homozygous and compound heterozygous change in patients with Canavan Disease (PMID: 20301412, 8023850, 10909858). Experimental studies have shown that this variant causes loss of ASPA enzyme activity (PMID: 22750302, 8023850). This variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.02% (57/282352) and thus is presumed to be rare. It affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.914C>A (p.Ala305Glu) variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University Hospital Muenster	Aug 29, 2022	ACMG categories: PS3,PM1,PM2,PP3,PP4,PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 08, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 12, 2019	NM_000049.2(ASPA):c.914C>A(A305E) is classified as pathogenic in the context of Canavan disease and can be associated with a severe or mild form of the disease. Sources cited for classification include the following: PMID 22850825, 22750302, 8023850 and 7668285. Classification of NM_000049.2(ASPA):c.914C>A(A305E) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Oct 03, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 26, 2018	The ASPA c.914C>A (p.Ala305Glu) variant is frequently reported in non-Jewish individuals with Canavan disease (CD). Across a selection of the available literature, the p.Ala305Glu variant has been identified in a homozygous state in eight patients with severe CD, in a compound heterozygous state in five patients with mild to classic CD, and in a heterozygous state in 13 patients in whom a second variant was not identified (Kaul et al. 1994; Shaag et al. 2005; Yalcinkaya et al. 2005; Janson et al. 2006; Sarret et al. 2015; Merrill et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.000372 in the European (non-Finnish) population of the Genome Aggregation Database. Cultured fibroblasts from affected individuals demonstrated negligible (0-5%) ASPA enzymatic activity as compared to fibroblasts from healthy controls (Yalcinkaya et al. 2005; Janson et al. 2006). Significantly reduced ASPA activity was also confirmed in various cell lines (Kaul et al. 1994; Janson et al. 2006; Sommer et al. 2012; Zano et al. 2013). Based on the collective evidence, the p.Ala305Glu 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, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 305 of the ASPA protein (p.Ala305Glu). This variant is present in population databases (rs28940574, gnomAD 0.04%). This missense change has been observed in individual(s) with Canavan disease (PMID: 8023850, 10909858, 16217711, 22850825). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2607). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ASPA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ASPA function (PMID: 8023850, 22750302). For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	One pathogenic variant, p.Ala305Glu, accounts for 30%-60% of pathogenic variants in non-Ashkenazi Jewish populations and approximately 1% of pathogenic variants in the Ashkenazi Jewish population. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 22, 2022	- -

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	Feb 09, 2021	Functional analysis found that A305E is associated with significantly reduced enzyme activity compared to wild type (Sommer et al., 2012; Zano et al., 2013); This variant is associated with the following publications: (PMID: 25497124, 30834272, 16217711, 16437572, 28101991, 27927234, 7668285, 22850825, 8023850, 26586007, 21228398, 23233226, 22750302) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 09, 2021

The c.914C>A (p.A305E) alteration is located in exon 6 (coding exon 6) of the ASPA gene. This alteration results from a C to A substitution at nucleotide position 914, causing the alanine (A) at amino acid position 305 to be replaced by a glutamic acid (E). Based on data from the Genome Aggregation Database (gnomAD) database, the ASPA c.914C>A alteration was observed in 0.02% (57/282352) of total alleles studied, with a frequency of 0.04% (48/128892) in the European (non-Finnish) subpopulation. This alteration has been reported in the homozygous and compound heterozygous states in patients with Canavan disease and is a common mutation that accounts for up to 60% of mutations in non-Ashkenazi Jewish populations (Kaul, 1994; Shaag, 1995; Kaul, 1996). This amino acid position is well conserved in available vertebrate species. Multiple in vitro studies have demonstrated that this mutation results in loss of ASPA protein activity, displays loss of flexibility resulting in decreased binding affinity, and can affect the order in the β-sheet structure at the C-terminus of the ASPA protein (Kaul, 1994; Sommer, 2012; Sreevishnupriya, 2012; Zano, 2013). The p.A305E alteration is predicted to be deleterious by in silico analysis. 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

Mar 23, 2017

Variant summary: The ASPA c.914C>A (p.Ala305Glu) variant involves the alteration of a conserved nucleotide and 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome for this variant. These predictions are supported by a functional study, Kaul_1994, that indicates the variant eliminates ASPA enzyme activity in COS1 transfected cells. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 27/117066 (1/4336), which does not exceed the estimated maximal expected allele frequency for a pathogenic ASPA variant of 1/126. The variant of interest has been reported in multiple affected individuals, both homozygotes and compound heterozygotes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.41	T;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.0	N;N
REVEL	Pathogenic	0.70
Sift	Benign	0.030	D;D
Sift4G	Benign	0.13	T;T
Polyphen		1.0	D;D
Vest4		0.50
MVP		1.0
MPC		0.44
ClinPred		0.25	T
GERP RS		5.8
Varity_R		0.66
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: rs28940574; hg19: chr17-3402354;