rs104894548

Positions:

• chr17-3483520-T-C

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.454T>C​(p.Cys152Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. C152W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASPA NM_000049.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.61

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 strand (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 chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 17-3483520-T-C is Pathogenic according to our data. Variant chr17-3483520-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASPA	NM_000049.4	c.454T>C	p.Cys152Arg	missense_variant	3/6	ENST00000263080.3	NP_000040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASPA	ENST00000263080.3	c.454T>C	p.Cys152Arg	missense_variant	3/6	1	NM_000049.4	ENSP00000263080.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spongy degeneration of central nervous system Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	Same or different nucleotide change resulting in same amino acid change has been previously reported to be associated with ASPA related disorder (ClinVar ID: VCV000002606 ). The variant has been reported to be in trans with a pathogenic variant as homozygous in at least one similarly affected unrelated individual(PMID: 7599639). Different pathogenic/likely pathogenic amino acid change has been reported with supporting evidence at the same codon (PMID:8659549,12638939). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.917>=0.6, 3CNET: 0.887>=0.75). It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 06, 2023	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 152 of the ASPA protein (p.Cys152Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Canavan disease (PMID: 7599639). ClinVar contains an entry for this variant (Variation ID: 2606). 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: 7599639, 22850825). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1995	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 15, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Oct 22, 2012	The observed variant c.454T>C (p.Cys152Arg) is not reported in 1000 Genomes and ExAC databases. The in silico prediction of the variant is disease causing by MutationTaster2, damaging by SIFT and probably damaging by PolyPhen2. -

Canavan Disease, Familial Form Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Sep 20, 2023

Variant summary: ASPA c.454T>C (p.Cys152Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251422 control chromosomes (gnomAD). c.454T>C has been reported in the literature in the homozygous state in an individual affected with Canavan Disease (Kaul_1995). These data indicate that the variant may be associated with disease. Publications report experimental evidence evaluating an impact on protein function in vitro and found the variant results in a severe loss in enzyme activity, approximately 0.5% of the wild type protein, and has reduced thermal and conformational stability (Kaul_1995, Zano_2013). Additionally, other variants affecting the same amino acid (i.e. C152W, C152Y) have been observed in affected individuals (HGMD database), at least one of which (C152W) has also been shown to have impaired enzyme activity in a functional study (Zano_2013), suggesting Cys152 is important for enzyme function. The following publications have been ascertained in the context of this evaluation (PMID: 7599639, 22850825). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. 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	0.92
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.78	.;T
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;M
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	D;D
Vest4		0.94
MutPred		0.94		Loss of sheet (P = 0.007);Loss of sheet (P = 0.007);
MVP		0.98
MPC		0.49
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.91
gMVP		0.97

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

LitVar

Other links and lift over

dbSNP: rs104894548; hg19: chr17-3386814; COSMIC: COSV105837442;