chr17-3476178-GCTGAAGAACATATACAAAAGGTTGCTATCTTTGGAGGAACCCATGGGAATGAGCTAACCGGAGTATTTCTGGTTAAGCATTGGCTAGAGAATGGCGCTGAGATTCAGAGAACAGGGCTGGAGGTAAAACCATTTATTACTAACCCCAGAGCAGTGAAGAAGTGTACCAGATATATTGACTGTGACC-G

Variant names:

• chr17-3476178-GCTGAAGAACATATACAAAAGGTTGCTATCTTTGGAGGAACCCATGGGAATGAGCTAACCGGAGTATTTCTGGTTAAGCATTGGCTAGAGAATGGCGCTGAGATTCAGAGAACAGGGCTGGAGGTAAAACCATTTATTACTAACCCCAGAGCAGTGAAGAAGTGTACCAGATATATTGACTGTGACC-G
• NM_000049.4:c.20_205del

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM4 PP5_Moderate

The NM_000049.4(ASPA):​c.20_205del​(p.Ala7_Leu69delinsVal) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A7A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASPA NM_000049.4 disruptive_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.93
• Publications: 0 publications found

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]

SPATA22 Gene-Disease associations (from GenCC):

• infertility disorder

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000049.4.
• PP5: Variant 17-3476178-GCTGAAGAACATATACAAAAGGTTGCTATCTTTGGAGGAACCCATGGGAATGAGCTAACCGGAGTATTTCTGGTTAAGCATTGGCTAGAGAATGGCGCTGAGATTCAGAGAACAGGGCTGGAGGTAAAACCATTTATTACTAACCCCAGAGCAGTGAAGAAGTGTACCAGATATATTGACTGTGACC-G is Pathogenic according to our data. Variant chr17-3476178-GCTGAAGAACATATACAAAAGGTTGCTATCTTTGGAGGAACCCATGGGAATGAGCTAACCGGAGTATTTCTGGTTAAGCATTGGCTAGAGAATGGCGCTGAGATTCAGAGAACAGGGCTGGAGGTAAAACCATTTATTACTAACCCCAGAGCAGTGAAGAAGTGTACCAGATATATTGACTGTGACC-G is described in ClinVar as [Pathogenic]. Clinvar id is 2418719.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPA	NM_000049.4	c.20_205del	p.Ala7_Leu69delinsVal	disruptive_inframe_deletion	Exon 1 of 6	ENST00000263080.3	NP_000040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASPA	ENST00000263080.3	c.20_205del	p.Ala7_Leu69delinsVal	disruptive_inframe_deletion	Exon 1 of 6	1	NM_000049.4	ENSP00000263080.2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spongy degeneration of central nervous system Pathogenic:1

Oct 19, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.20_205del, is a complex sequence change that results in the deletion of 63 amino acid(s) in the ASPA protein (p.Ala7_Leu69delinsVal). This variant has not been reported in the literature in individuals affected with ASPA-related conditions. This variant disrupts a region of the ASPA protein in which other variant(s) (p.Ile16Thr) have been determined to be pathogenic (PMID: 8659549, 12638939). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=28/172	disease causing (long InDel)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr17-3379472;