rs770706390

Positions:

• chr17-3483569-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_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 Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: ASPA NM_000049.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 5.98

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 18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain 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 ClinVar as [Likely_pathogenic]. Clinvar id is 813438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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	UniProt
ASPA	NM_000049.4	c.503G>A	p.Arg168His	missense_variant	3/6	ENST00000263080.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPA	ENST00000263080.3	c.503G>A	p.Arg168His	missense_variant	3/6	1	NM_000049.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152102 Hom.: 0 Cov.: 32

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: 13 AN: 251402 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135864

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: 50 AN: 1461566 Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 26 AN XY: 727112

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: 3 AN: 152102 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74294

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.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000988 AC: 12

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spongy degeneration of central nervous system Pathogenic:9

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	Baylor Genetics	Mar 21, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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. -
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	Revvity Omics, Revvity	Mar 02, 2021	- -
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, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 17, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
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. -

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	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	23
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D;D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.53	T
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	T
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

Other links and lift over

dbSNP: rs770706390; hg19: chr17-3386863; COSMIC: COSV53981194;