17-3489250-CT-TA

Variant names:

• chr17-3489250-CT-TA
• NM_000049.4:c.542_543delCTinsTA
• ASPA p.Pro181Leu

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS1 PM1 PM5 PP2

The NM_000049.4(ASPA):​c.542_543delCTinsTA​(p.Pro181Leu) variant causes a missense change involving the alteration of a 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 MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P181T) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ASPA NM_000049.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.29
• 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):

• genetic infertility

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

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PS1: Transcript NM_000049.4 (ASPA) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000049.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-3489249-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 188940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 48 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: 0.47868 (below the threshold of 3.09). Trascript score misZ: 1.2423 (below the threshold of 3.09). GenCC associations: The gene is linked to severe Canavan disease, Canavan disease, mild Canavan disease.

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.542_543delCTinsTA	p.Pro181Leu	missense	N/A	NP_000040.1	Q6FH48
	ASPA	NM_001128085.1		c.542_543delCTinsTA	p.Pro181Leu	missense	N/A	NP_001121557.1	P45381
	SPATA22	NM_001321337.2		c.-73-19853_-73-19852delAGinsTA		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.542_543delCTinsTA	p.Pro181Leu	missense	N/A	ENSP00000263080.2	P45381
	ASPA	ENST00000456349.6	TSL:1	c.542_543delCTinsTA	p.Pro181Leu	missense	N/A	ENSP00000409976.2	P45381
	ASPA	ENST00000858436.1		c.542_543delCTinsTA	p.Pro181Leu	missense	N/A	ENSP00000528495.1

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.3

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr17-3392544;