rs386833420

Variant names:

• chr4-177440352-GCTCT-G
• rs386833420
• NM_000027.4:c.198_201delAGAG

Your query was ambiguous. Multiple possible variants found:

• chr4-177440352-GCTCT-G
• chr4-177440352-GCTCT-GCT
• chr4-177440352-GCTCT-GCTCTCT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000027.4(AGA):​c.198_201delAGAG​(p.Arg66SerfsTer7) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: AGA NM_000027.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.55

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 18 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 4-177440352-GCTCT-G is Pathogenic according to our data. Variant chr4-177440352-GCTCT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2680792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGA	NM_000027.4	c.198_201delAGAG	p.Arg66SerfsTer7	frameshift_variant	Exon 2 of 9	ENST00000264595.7	NP_000018.2
AGA	NM_001171988.2	c.198_201delAGAG	p.Arg66SerfsTer7	frameshift_variant	Exon 2 of 9		NP_001165459.1
AGA	XM_047449722.1	c.198_201delAGAG	p.Arg66SerfsTer7	frameshift_variant	Exon 2 of 7		XP_047305678.1
AGA	NR_033655.2	n.260_263delAGAG		non_coding_transcript_exon_variant	Exon 2 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGA	ENST00000264595.7	c.198_201delAGAG	p.Arg66SerfsTer7	frameshift_variant	Exon 2 of 9	1	NM_000027.4	ENSP00000264595.2
AGA	ENST00000506853.5	n.232_235delAGAG		non_coding_transcript_exon_variant	Exon 2 of 6	2
AGA	ENST00000510955.5	n.232_235delAGAG		non_coding_transcript_exon_variant	Exon 2 of 4	2
AGA	ENST00000511231.1	n.232_235delAGAG		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aspartylglucosaminuria Pathogenic:2

Mar 07, 2024

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.Arg66Serfs*7) in the AGA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AGA are known to be pathogenic (PMID: 7627186, 11309371). This variant is present in population databases (rs779157725, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with AGA-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Jan 11, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs386833420; hg19: chr4-178361506;