rs770706390

Positions:

chr17-3483569-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000049.4(ASPA):c.503G>A(p.Arg168His) variant causes a missense change. The variant allele was found at a frequency of 0.0000328 in 1,613,668 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R168C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

ASPA
NM_000049.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 5.98

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 18 ACMG points.

PM1

In a binding_site (size 4) 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 chr17-3483568-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.973

PP5

Variant 17-3483569-G-A is Pathogenic according to our data. Variant chr17-3483569-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 550697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-3483569-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASPA	NM_000049.4 linkuse as main transcript	c.503G>A	p.Arg168His	missense_variant	3/6	ENST00000263080.3	NP_000040.1	P45381Q6FH48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASPA	ENST00000263080.3 linkuse as main transcript	c.503G>A	p.Arg168His	missense_variant	3/6	1	NM_000049.4	ENSP00000263080.2		P45381

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000517

AC:

AN:

251402

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000578

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:

0.0000792

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000342

AC:

AN:

1461566

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

727112

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.0000187

Gnomad4 NFE exome

AF:

0.0000378

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152102

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000324

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000988

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Spongy degeneration of central nervous system

Pathogenic:10

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 17, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 168 of the ASPA protein (p.Arg168His). This variant is present in population databases (rs770706390, gnomAD 0.009%). This missense change has been observed in individuals with Canavan disease (PMID: 10909858, 21520333, 28101991). ClinVar contains an entry for this variant (Variation ID: 550697). 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: 22750302). This variant disrupts the p.Arg168 amino acid residue in ASPA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8659549, 16854607). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	A Homozygote Missense variant c.503G>A in Exon 3 of the ASPA gene that results in the amino acid substitution p.Arg168His was identified. The observed variant has a minor allele frequency of 0.00005% in gnomAD exomes and is novel in genomes. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variant ID : 550697]. The observed variation has previously been reported for Canavan disease by Mendes, Marisa I., et al., 2017. Functional assessments proves the pathogenicity of the variant by Sommer, Anke, and Jörn Oliver Sass. , 2012. For these reasons this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 02, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 03, 2021	NM_000049.2(ASPA):c.503G>A(R168H) is a missense variant classified as likely pathogenic in the context of Canavan disease. R168H has been observed in cases with relevant disease (PMID: 10909858, 23971085, 28101991). Functional assessments of this variant are available in the literature (PMID: 22750302). Internal structural analysis of the variant is supportive of pathogenicity. R168H has been observed in population frequency databases (gnomAD: NFE 0.01%). In summary, NM_000049.2(ASPA):c.503G>A(R168H) is a missense variant that has internal structural support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Apr 05, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.R168H in ASPA (NM_000049.2) has been observed in several individuals affected with Canavan disease (E A Sistermans et al, 2000; Marisa I Mendes et al, 2017). This variant has been reported to affect ASPA protein function (A Sommer et al, 2012). This missense has been submitted to ClinVar as Pathogenic/Likely Pathogenic. The p.R168H variant is observed as heterozygous in 13 (0.005%) alleles from individuals of all background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.R168H missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.503 in ASPA is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 23, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 21, 2024	- -

Canavan Disease, Familial Form

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Nov 10, 2022

Variant summary: ASPA c.503G>A (p.Arg168His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251402 control chromosomes. This frequency is not higher than expected for a pathogenic variant in ASPA causing Canavan Disease (5.2e-05 vs 0.0079), allowing no conclusion about variant significance. c.503G>A has been reported in the literature in individuals affected with Canavan Disease in the homozygous and heterozygous state (Sistermans_2000, Mendes_2017). These data indicate that the variant is likely to be associated with disease. The variant has been reported to have loss of ASPA activity in transfected HEK293 cells (Sommer_2012) . Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=2) and likely pathogenic (n=4). 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

0.60

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.23

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

D;D

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.83

.;T

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

0.81

MutationAssessor

Uncertain

2.6

M;M

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-2.0

N;N

REVEL

Pathogenic

0.75

Sift

Benign

0.030

D;D

Sift4G

Benign

0.098

T;T

Polyphen

0.98

D;D

Vest4

0.85

MutPred

0.89

Gain of ubiquitination at K163 (P = 0.0527);Gain of ubiquitination at K163 (P = 0.0527);

MVP

0.99

MPC

0.31

ClinPred

0.48

GERP RS

3.4

Varity_R

0.69

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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