rs386833435

Positions:

• chr4-177434399-CA-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000027.4(AGA):​c.788del​(p.Leu263Ter) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: AGA NM_000027.4 frameshift
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.85

Genes affected

AGA (HGNC:318): (aspartylglucosaminidase) This gene encodes a member of the N-terminal nucleophile (Ntn) hydrolase family of proteins. The encoded preproprotein is proteolytically processed to generate alpha and beta chains that comprise the mature enzyme. This enzyme is involved in the catabolism of N-linked oligosaccharides of glycoproteins. It cleaves asparagine from N-acetylglucosamines as one of the final steps in the lysosomal breakdown of glycoproteins. Mutations in this gene are associated with the lysosomal storage disease aspartylglycosaminuria that results in progressive neurodegeneration. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is subject to proteolytic processing. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-177434399-CA-C is Pathogenic according to our data. Variant chr4-177434399-CA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55954.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr4-177434399-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGA	NM_000027.4	c.788del	p.Leu263Ter	frameshift_variant	7/9	ENST00000264595.7	NP_000018.2
AGA	NM_001171988.2	c.758del	p.Leu253Ter	frameshift_variant	7/9		NP_001165459.1
AGA	XM_047449722.1	c.*82del		3_prime_UTR_variant	7/7		XP_047305678.1
AGA	NR_033655.2	n.774del		non_coding_transcript_exon_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGA	ENST00000264595.7	c.788del	p.Leu263Ter	frameshift_variant	7/9	1	NM_000027.4	ENSP00000264595	P1
AGA	ENST00000502310.5	c.359del	p.Leu120Ter	frameshift_variant	4/5	5		ENSP00000423798
AGA	ENST00000506853.5	n.746del		non_coding_transcript_exon_variant	6/6	2
AGA	ENST00000510635.1			downstream_gene_variant		1		ENSP00000421471

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Aspartylglucosaminuria Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

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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: rs386833435; hg19: chr4-178355553;