rs766720790

Variant names:

• chr17-3499015-AAAAG-A
• rs766720790
• NM_000049.4:c.876_879delAGAA

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000049.4(ASPA):​c.876_879delAGAA​(p.Glu293LeufsTer8) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000356 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: ASPA NM_000049.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 7.14

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 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-3499015-AAAAG-A is Pathogenic according to our data. Variant chr17-3499015-AAAAG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-3499015-AAAAG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASPA	NM_000049.4	c.876_879delAGAA	p.Glu293LeufsTer8	frameshift_variant	Exon 6 of 6	ENST00000263080.3	NP_000040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASPA	ENST00000263080.3	c.876_879delAGAA	p.Glu293LeufsTer8	frameshift_variant	Exon 6 of 6	1	NM_000049.4	ENSP00000263080.2
ASPA	ENST00000456349.6	c.876_879delAGAA	p.Glu293LeufsTer8	frameshift_variant	Exon 7 of 7	1		ENSP00000409976.2
SPATA22	ENST00000541913.5	c.-74+14393_-74+14396delCTTT		intron_variant	Intron 1 of 8	2		ENSP00000441920.1
SPATA22	ENST00000570318.1	c.-74+14592_-74+14595delCTTT		intron_variant	Intron 1 of 1	2		ENSP00000459147.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251438 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135900

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: 0.0000356 AC: 52 AN: 1461886 Hom.: 0 AF XY: 0.0000358 AC XY: 26 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000597

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: 0.0000423

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spongy degeneration of central nervous system Pathogenic:7

Dec 13, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Glu293Leufs*8) in the ASPA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 21 amino acid(s) of the ASPA protein. This variant is present in population databases (rs766720790, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with Canavan disease (PMID: 8659549). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 876 delAGAA. ClinVar contains an entry for this variant (Variation ID: 371665). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects ASPA function (PMID: 8659549). This variant disrupts the p.Ala305 amino acid residue in ASPA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8023850, 10909858, 16217711, 22850825). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Nov 19, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 13, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu293fs variant in ASPA has been reported in 3 individuals with Canavan d isease, including at least one compound heterozygote (Kaul 1996). This variant h as been identified in 1/66340 of European chromosomes by the Exome Aggregation C onsortium (ExAC, http://exac.broadinstitute.org). In vitro assays suggest that t his variant abolished ASPA protein activity (Kaul 1996); however, these types of assays may not accurately represent biological function. This variant is predic ted to cause a frameshift, which alters the protein?s amino acid sequence beginn ing at position 293 and leads to a premature termination codon 8 amino acids dow nstream. This termination codon occurs within the last exon and is more likely t o escape nonsense mediated decay (NMD) and result in a truncated protein. In sum mary, although additional studies are required to fully establish its clinical s ignificance, the p.Glu293fs variant is likely pathogenic. -

Nov 11, 2016

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 20, 2019

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Sep 17, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published expression studies found this variant is associated with undetectable to <0.5% of residual enzyme activity compared to wild-type (PMID: 8659549); Frameshift variant predicted to result in abnormal protein length as the last 21 amino acid(s) are replaced with 7 different amino acid(s), and other similar variants have been reported in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34426522, 31589614, 10407784, 12638939, 8659549, 34302356) -

Canavan Disease, Familial Form Pathogenic:1

Mar 13, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ASPA c.876_879delAGAA (p.Glu293LeufsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 8e-06 in 251438 control chromosomes. c.876_879delAGAA has been reported in the literature in individuals affected with Canavan Disease (example, Kaul_1996, Zeng_2002). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in undetectable ASPA enzyme activity in-vitro (example, Kaul_1996). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs766720790; hg19: chr17-3402309;