17-3483575-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PP2PP5BP4

The NM_000049.4(ASPA):c.509T>C(p.Ile170Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000709 in 1,613,502 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00071 ( 1 hom. )

Consequence

ASPA
NM_000049.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:9

Conservation

PhyloP100: 6.24

Publications

13 publications found

Variant links:

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]

ASPA links:

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

SPATA22 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 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, 5 uncertain in NM_000049.4

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 48 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: 0.47868 (below the threshold of 3.09). Trascript score misZ: 1.2423 (below the threshold of 3.09). GenCC associations: The gene is linked to Canavan disease, mild Canavan disease, severe Canavan disease.

PP5

Variant 17-3483575-T-C is Pathogenic according to our data. Variant chr17-3483575-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 322633.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BP4

Computational evidence support a benign effect (MetaRNN=0.3882036). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPA	NM_000049.4 link	c.509T>C	p.Ile170Thr	missense_variant	Exon 3 of 6	ENST00000263080.3	NP_000040.1	P45381Q6FH48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASPA	ENST00000263080.3 link	c.509T>C	p.Ile170Thr	missense_variant	Exon 3 of 6	1	NM_000049.4	ENSP00000263080.2		P45381

Frequencies

GnomAD3 genomes

AF:

0.000657

AC:

100

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000964

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00134

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000370

AC:

AN:

251418

AF XY:

0.000302

show subpopulations

Gnomad AFR exome

AF:

0.000185

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:

0.000774

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000714

AC:

1044

AN:

1461254

Hom.:

Cov.:

AF XY:

0.000619

AC XY:

450

AN XY:

727000

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.0000936

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000897

AC:

997

AN:

1111440

Other (OTH)

AF:

0.000547

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

102

154

205

256

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000657

AC:

100

AN:

152248

Hom.:

Cov.:

AF XY:

0.000565

AC XY:

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.0000964

AC:

AN:

41474

American (AMR)

AF:

0.000131

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5206

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00134

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000786

Hom.:

Bravo

AF:

0.000563

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.000313

AC:

EpiCase

AF:

0.00136

EpiControl

AF:

0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Spongy degeneration of central nervous system

Pathogenic:1Uncertain:5

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 170 of the ASPA protein (p.Ile170Thr). This variant is present in population databases (rs144321760, gnomAD 0.09%). This missense change has been observed in individual(s) with Canavan disease (PMID: 28101991, 29453510). ClinVar contains an entry for this variant (Variation ID: 322633). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ASPA protein function. Experimental studies have shown that this missense change affects ASPA function (PMID: 28101991). For these reasons, this variant has been classified as Pathogenic. -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 06, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Nov 07, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 14, 2018

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Uncertain:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Canavan Disease, Familial Form

Pathogenic:1

May 19, 2025

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ASPA c.509T>C (p.Ile170Thr) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 0.00071 in 1613502 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in ASPA causing Canavan Disease (0.00071 vs 0.0079), allowing no conclusion about variant significance. c.509T>C has been reported in the literature as homozygous and presumed compound heterozygous genotypes in at least 3 individuals with mild elevations in levels of N-acetyl aspartate and variable presentations of Canvan Disease (example, Mendes_2017, Coene_2018). These reports do not provide unequivocal conclusions about association of the variant with Canavan Disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal Aspartocyclase enzyme activity in HEK293 transfected cells (5.5% of WT), although the authors interpret this finding as having relatively higher residual enzyme activity (Mendes_2017). ClinVar contains an entry for this variant (Variation ID: 322633). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Intellectual disability

Uncertain:1

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.88

D;D

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.88

.;D

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.39

T;T

MetaSVM

Pathogenic

0.93

MutationAssessor

Benign

1.9

L;L

PhyloP100

6.2

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.9

D;D

REVEL

Uncertain

0.63

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.037

D;D

Polyphen

0.21

B;B

Vest4

0.55

MVP

0.93

MPC

0.20

ClinPred

0.21

GERP RS

5.4

Varity_R

0.56

gMVP

0.79

Mutation Taster

=76/24

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over