17-3476206-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000049.4(ASPA):c.47T>C(p.Ile16Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,802 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 (★★). Synonymous variant affecting the same amino acid position (i.e. I16I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ASPA NM_000049.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.79

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 16 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 17-3476206-T-C is Pathogenic according to our data. Variant chr17-3476206-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 550560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-3476206-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASPA	NM_000049.4	c.47T>C	p.Ile16Thr	missense_variant	1/6	ENST00000263080.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPA	ENST00000263080.3	c.47T>C	p.Ile16Thr	missense_variant	1/6	1	NM_000049.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251420 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135886

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461802 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727198

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.000119

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:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 10, 2022	The p.Ile16Thr variant in ASPA has been reported in compound heterozygous state with another pathogenic ASPA variant in 3 individuals with Canavan Disease (Kaul 1996 PMID: 8659549, Elpeleg 1999 PMID: 10407784, Zeng 2002 PMID: 12638939). It at least 1 individual, the Ile16Thr variant was confirmed to be in trans. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 550560) and has been identified in 0.002% (2/113756) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies of enzyme activity provide evidence that this variant affects protein function, as its enzymatic activity was 0.4% of the wild type allele (Kaul 1996 PMID: 8659549). Computational prediction tools and conservation analyses do not provide evidence for or against an effect to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Canavan Disease. ACMG/AMP Criteria applied: PM3_Strong, PM2_Supporting, PS3_Moderate. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 01, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 14, 2022	This missense change has been observed in individual(s) with Canavan disease (PMID: 8659549, 12638939). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ASPA function (PMID: 8659549). 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. ClinVar contains an entry for this variant (Variation ID: 550560). This variant is present in population databases (rs769653717, gnomAD 0.002%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 16 of the ASPA protein (p.Ile16Thr). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 09, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;D;D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;.;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.59	T
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		0.99	.;D;D
Vest4		0.95, 0.96
MutPred		0.94		Loss of stability (P = 0.0064);Loss of stability (P = 0.0064);Loss of stability (P = 0.0064);
MVP		0.96
MPC		0.33
ClinPred		0.96	D
GERP RS		5.4
Varity_R		0.77
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: rs769653717; hg19: chr17-3379500;