rs104894553

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1PM2PM5PP2PP5_Very_Strong

The NM_000049.4(ASPA):c.212G>A(p.Arg71His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,613,924 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R71C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

ASPA
NM_000049.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12O:1

Conservation

PhyloP100: 9.72

Publications

16 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: Pathogenic. The variant received 15 ACMG points.

PM1

In a helix (size 2) in uniprot entity ACY2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000049.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-3476370-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1503500.

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 17-3476371-G-A is Pathogenic according to our data. Variant chr17-3476371-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2616.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 link	c.212G>A	p.Arg71His	missense_variant	Exon 1 of 6	ENST00000263080.3	NP_000040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASPA	ENST00000263080.3 link	c.212G>A	p.Arg71His	missense_variant	Exon 1 of 6	1	NM_000049.4	ENSP00000263080.2

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00141

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000219

AC:

AN:

251372

AF XY:

0.000213

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00195

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000109

AC:

160

AN:

1461760

Hom.:

Cov.:

AF XY:

0.000106

AC XY:

AN XY:

727176

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00204

AC:

109

AN:

53336

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000414

AC:

AN:

1111984

Other (OTH)

AF:

0.0000331

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000138

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41412

American (AMR)

AF:

0.000131

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00141

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68042

Other (OTH)

AF:

0.000479

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.523

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:

0.000143

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.000189

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Spongy degeneration of central nervous system

Pathogenic:6Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Aug 29, 2018

Counsyl

Significance:Likely pathogenic

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.

Mar 28, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ASPA c.212G>A (p.Arg71His) variant has been reported in three studies and is found in a total of three individuals with a mild form of Canavan disease including one individual in a homozygous state and two sisters in a compound heterozygous state (Janson et al. 2006; Velinov et al. 2007). Control data are unavailable for this variant, which is reported at a frequency of 0.00197 in the European (Finnish) population of the Exome Aggregation Consortium. Functional studies in individual fibroblasts showed only 0% to 5% of ASPA activity compared to wild type (Janson et al. 2006). Bitto et al. (2007) determined the crystal structure of APSA and showed that the Arg71 residue lies in the ASPA active site and proposed a role in substrate binding. Hershfield et al. (2007) used homology-based modeling to analyze the function of the p.Arg71His variant and also concluded that Arg71 was located in the active site and was involved in substrate binding. Expression studies in P. pastoris by Zano et al. (2013) showed that the variant enzyme had 11% of wild type activity and reduced stability. The Arg71 residue is highly conserved. Based on the evidence, the p.Arg71His variant is classified as likely pathogenic for Canavan disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 71 of the ASPA protein (p.Arg71His). This variant is present in population databases (rs104894553, gnomAD 0.2%). This missense change has been observed in individual(s) with Canavan disease (PMID: 16437572, 18070137, 25107638). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2616). 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) 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: 16437572, 22850825). For these reasons, this variant has been classified as Pathogenic.

Jan 31, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 07, 2021

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Pathogenic:3

Jan 27, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate loss of enzymatic activity (PMID: 16437572, 22850825); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22850825, 17194761, 18070137, 16437572, 25668701, 34426522, 32975148, 25003821, 25107638, 23971085, 39628365, 38740822, 38718669)

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mild Canavan disease

Pathogenic:1

Mar 01, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Inborn genetic diseases

Pathogenic:1

Jul 01, 2017

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R71H pathogenic mutation (also known as c.212G>A), located in coding exon 1 of the ASPA gene, results from a G to A substitution at nucleotide position 212. The arginine at codon 71 is replaced by histidine, an amino acid with highly similar properties. This alteration has been detected in trans with a pathogenic mutation (p.Y231*) in ASPA by our laboratory. This mutation was identified in conjunction with another known mutation p.A305E in two siblings who presented with mild form of Canavan disease; ASPA enzymatic activity was significantly low in fibroblasts from these siblings (Janson CG et al. Ann. Neurol., 2006 Feb;59:428-31). A homozygous p.R71H mutation was also reported in another patient with mild Canavan disease (Velinov M et al. Clin. Genet., 2008 Mar;73:288-9). Structural analysis revealed that the arginine residue likely stabilizes substrate binding and may guide NAA to the active site (Bitto E et al. Proc. Natl. Acad. Sci. U.S.A., 2007 Jan;104:456-61). In vitro studies showed that R71H mutant protein has reduced catalytic activity (Janson CG et al. Ann. Neurol., 2006 Feb;59:428-31; Zano S et al. J. Inherit. Metab. Dis., 2013 Jan;36:1-6). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Canavan Disease, Familial Form

Pathogenic:1

Feb 24, 2025

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ASPA c.212G>A (p.Arg71His) results in a non-conservative amino acid change located in the Succinylglutamate desuccinylase/Aspartoacylase catalytic domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 251372 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ASPA causing Canavan Disease (0.00022 vs 0.0079), allowing no conclusion about variant significance. c.212G>A has been reported in the literature in multiple bi-allelic individuals affected with Canavan Disease (example: Velinov_2007,Janson_2006). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Janson_2006). The following publications have been ascertained in the context of this evaluation (PMID: 18070137, 16437572). ClinVar contains an entry for this variant (Variation ID: 2616). Based on the evidence outlined above, the variant was classified as pathogenic.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

D;D;D

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;.;D

M_CAP

Pathogenic

0.38

MetaRNN

Uncertain

0.68

D;D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Benign

0.0

.;M;M

PhyloP100

9.7

PrimateAI

Uncertain

0.48

PROVEAN

Benign

0.0

.;D;D

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;D;D

Sift4G

Uncertain

0.0030

D;D;D

Vest4

0.0

ClinPred

0.80

GERP RS

5.5

PromoterAI

-0.18

Neutral

(source)

Varity_R

0.69

gMVP

0.96

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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