rs104894552

Positions:

• chr17-3498892-A-T

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.746A>T​(p.Asp249Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,424,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. D249N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: ASPA NM_000049.4 missense, splice_region
• Scores: Splicing: ADA: 0.9078
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 8.94

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 hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000049.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 17-3498892-A-T is Pathogenic according to our data. Variant chr17-3498892-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-3498892-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASPA	NM_000049.4	c.746A>T	p.Asp249Val	missense_variant, splice_region_variant	6/6	ENST00000263080.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASPA	ENST00000263080.3	c.746A>T	p.Asp249Val	missense_variant, splice_region_variant	6/6	1	NM_000049.4	P1
ASPA	ENST00000456349.6	c.746A>T	p.Asp249Val	missense_variant, splice_region_variant	7/7	1		P1
SPATA22	ENST00000541913.5	c.-74+14520T>A		intron_variant		2
SPATA22	ENST00000570318.1	c.-74+14719T>A		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000619 AC: 14 AN: 226310 Hom.: 0 AF XY: 0.0000653 AC XY: 8 AN XY: 122590

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: 0.000124

Gnomad OTH exome AF: 0.000185

GnomAD4 exome AF: 0.0000204 AC: 29 AN: 1424098 Hom.: 0 Cov.: 30 AF XY: 0.0000170 AC XY: 12 AN XY: 705260

Gnomad4 AFR exome AF: 0.00

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: 0.0000380

Gnomad4 NFE exome AF: 0.0000192

Gnomad4 OTH exome AF: 0.000102

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.000124 AC: 15

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

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	Counsyl	Nov 26, 2015	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 26, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 08, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ASPA function (PMID: 12638939, 17391648, 22850825). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 2615). This missense change has been observed in individual(s) with Canavan disease (PMID: 12205125, 12638939). This variant is present in population databases (rs104894552, gnomAD 0.01%). This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 249 of the ASPA protein (p.Asp249Val). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D;D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;M
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-6.8	D;D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	D;D
Vest4		0.95
MutPred		0.96		Loss of disorder (P = 0.0165);Loss of disorder (P = 0.0165);
MVP		0.99
MPC		0.43
ClinPred		0.86	D
GERP RS		5.8
Varity_R		0.89
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.91
dbscSNV1_RF	Benign	0.71
SpliceAI score (max)		0.050		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: rs104894552; hg19: chr17-3402186;