NM_000049.4:c.876_879delAGAA

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1_Strong PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV000711750: "In vitro assays suggest that this variant abolished ASPA protein activity (Kaul 1996)"; SCV001230214: Experimental studies have shown that this premature translational stop signal affects ASPA function (PMID:8659549).; SCV001519548: The most pronounced variant effect results in undetectable ASPA enzyme activity in-vitro (example, Kaul_1996).; SCV005888845: Published expression studies found this variant is associated with undetectable to <0.5% of residual enzyme activity compared to wild-type (PMID:8659549)".

• 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
• Publications: 1 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):

• genetic infertility

  Inheritance: AR Classification: MODERATE Submitted by: PanelApp Australia
• infertility disorder

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 18 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 12 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000711750: "In vitro assays suggest that this variant abolished ASPA protein activity (Kaul 1996)"; SCV001230214: Experimental studies have shown that this premature translational stop signal affects ASPA function (PMID: 8659549).; SCV001519548: The most pronounced variant effect results in undetectable ASPA enzyme activity in-vitro (example, Kaul_1996).; SCV005888845: Published expression studies found this variant is associated with undetectable to <0.5% of residual enzyme activity compared to wild-type (PMID: 8659549)
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 371665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000049.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPA	NM_000049.4	MANE Select	c.876_879delAGAA	p.Glu293LeufsTer8	frameshift	Exon 6 of 6	NP_000040.1	Q6FH48
	ASPA	NM_001128085.1		c.876_879delAGAA	p.Glu293LeufsTer8	frameshift	Exon 7 of 7	NP_001121557.1	P45381
	SPATA22	NM_001321337.2		c.-74+14393_-74+14396delCTTT		intron	N/A	NP_001308266.1	A0A140VJV9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPA	ENST00000263080.3	TSL:1 MANE Select	c.876_879delAGAA	p.Glu293LeufsTer8	frameshift	Exon 6 of 6	ENSP00000263080.2	P45381
	ASPA	ENST00000456349.6	TSL:1	c.876_879delAGAA	p.Glu293LeufsTer8	frameshift	Exon 7 of 7	ENSP00000409976.2	P45381
	ASPA	ENST00000858436.1		c.876_879delAGAA	p.Glu293LeufsTer8	frameshift	Exon 7 of 7	ENSP00000528495.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251438 AF XY: 0.00000736

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 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

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000423 AC: 47 AN: 1112004

Other (OTH) AF: 0.0000497 AC: 3 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Spongy degeneration of central nervous system (7)
1	-	-	Canavan Disease, Familial Form (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.1
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs766720790; hg19: chr17-3402309;