17-3476206-T-C

Position:

chr17-3476206-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_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 (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

ASPA
NM_000049.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 7.79

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.

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	Protein	UniProt
ASPA	NM_000049.4 linkuse as main transcript	c.47T>C	p.Ile16Thr	missense_variant	1/6	ENST00000263080.3	NP_000040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASPA	ENST00000263080.3 linkuse as main transcript	c.47T>C	p.Ile16Thr	missense_variant	1/6	1	NM_000049.4	ENSP00000263080	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251420

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135886

show subpopulations

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:

AN:

1461802

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727198

show subpopulations

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.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Spongy degeneration of central nervous system

Pathogenic:6

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	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 06, 2024	- -
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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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	Genome-Nilou Lab	Nov 07, 2021	- -

ASPA-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 01, 2024

The ASPA c.47T>C variant is predicted to result in the amino acid substitution p.Ile16Thr. This variant has been reported along with a second known pathogenic ASPA variant in two individuals with confirmed Canavan disease (Kaul et al. 1996. PubMed ID: 8659549; Zeng et al. 2002. PubMed ID: 12638939). The variants identified in the proband reported by Kaul et al. were confirmed to be in the compound heterozygous state. Additionally, this variant has been reported along with a second rare ASPA missense variant (p.Phe295Ser) in a patient with Canavan disease (Elpeleg and Shaag. 1999. PubMed ID: 10407784). In an expression study using COS1 cells, the p.Ile16Thr substitution was reported to decrease enzyme activity to <0.5% (Kaul et al. 1996. PubMed ID: 8659549). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It is classified as pathogenic or likely pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/550560/). Based on these observations, we interpret this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

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

LIST_S2

Uncertain

0.96

D;.;D

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.7

.;M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.6

.;D;D

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0030

.;D;D

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

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

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