rs104894553

Positions:

chr17-3476371-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM5PP5_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:10O:1

Conservation

PhyloP100: 9.72

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a binding_site (size 1) 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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-3476370-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 1786218.Status of the report is criteria_provided_single_submitter, 1 stars.

PP5

Variant 17-3476371-G-A is Pathogenic according to our data. Variant chr17-3476371-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-3476371-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASPA	NM_000049.4 linkuse as main transcript	c.212G>A	p.Arg71His	missense_variant	1/6	ENST00000263080.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPA	ENST00000263080.3 linkuse as main transcript	c.212G>A	p.Arg71His	missense_variant	1/6	1	NM_000049.4	P1

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

GnomAD3 exomes

AF:

0.000219

AC:

AN:

251372

Hom.:

AF XY:

0.000213

AC XY:

AN XY:

135860

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00204

Gnomad4 NFE exome

AF:

0.0000414

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000138

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00141

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.0000512

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:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Spongy degeneration of central nervous system

Pathogenic:6Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 25, 2023	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). 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: 16437572, 22850825). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2024	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Aug 29, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 18, 2021	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 03, 2022	Published functional studies demonstrate loss of enzymatic activity (Janson et al., 2006; Zano et al., 2013); 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, 25003821, 34426522, 25107638, 32975148) -

Mild Canavan disease

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2008

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 01, 2017

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. -

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

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

Pathogenic

3.4

.;M;M

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Uncertain

0.48

PROVEAN

Pathogenic

-4.7

.;D;D

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0020

.;D;D

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.99

MVP

0.98

MPC

0.15

ClinPred

0.80

GERP RS

5.5

Varity_R

0.69

gMVP

0.96

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over