rs386833436

Positions:

chr4-177434387-C-CA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000027.4(AGA):c.800dupT(p.Pro268fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,674 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

AGA
NM_000027.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 8.85

Variant links:

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]

AGA links:

AGA (HGNC:):

AGA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 4-177434387-C-CA is Pathogenic according to our data. Variant chr4-177434387-C-CA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGA	NM_000027.4 linkuse as main transcript	c.800dupT	p.Pro268fs	frameshift_variant	7/9	ENST00000264595.7	NP_000018.2	P20933
AGA	NM_001171988.2 linkuse as main transcript	c.770dupT	p.Pro258fs	frameshift_variant	7/9		NP_001165459.1	P20933
AGA	NR_033655.2 linkuse as main transcript	n.786dupT		non_coding_transcript_exon_variant	6/8
AGA	XM_047449722.1 linkuse as main transcript	c.*94dupT		downstream_gene_variant			XP_047305678.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
AGA	ENST00000264595.7 linkuse as main transcript	c.800dupT	p.Pro268fs	frameshift_variant	7/9	1	NM_000027.4	ENSP00000264595.2	P20933
AGA	ENST00000502310.5 linkuse as main transcript	c.371dupT	p.Pro125fs	frameshift_variant	4/5	5		ENSP00000423798.1	H0Y9C7
AGA	ENST00000506853.5 linkuse as main transcript	n.758dupT		non_coding_transcript_exon_variant	6/6	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251484

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000173

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:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461494

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727082

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000134

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000708

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Aspartylglucosaminuria

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 11, 2018	Variant summary: AGA c.800dupT (p.Pro268AlafsX52) 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 was observed with an allele freqyency of 2.8e-05 in 246258 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in AGA causing Aspartylglucosaminuria (2.8e-05 vs 0.0049), allowing no conclusion about variant significance. The variant, c.800dupT, has been reported in the literature in a homozygous individual affected with Aspartylglucosaminuria, who presented with less than 10% normal AGA activity (Ikonen_1991). These data indicate that the variant may be associated with disease. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "likely pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 12, 2016	- -
Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 15, 1991	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 10, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change creates a premature translational stop signal (p.Pro268Alafs*52) in the AGA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 79 amino acid(s) of the AGA protein. This variant is present in population databases (rs386833436, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with aspartylglucosaminuria (PMID: 1722323). ClinVar contains an entry for this variant (Variation ID: 225). 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 AGA function (PMID: 1722323, 11309371). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 11, 2021

The c.800dupT (p.P268Afs*52) alteration, located in exon 7 (coding exon 7) of the AGA gene, consists of a duplication of T at position 800, causing a translational frameshift with a predicted alternate stop codon after 52 amino acids. This alteration occurs at the 3' terminus of the AGA gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 79 amino acids of the protein. However, premature stop codons are typically deleterious in nature. Based on data from the Genome Aggregation Database (gnomAD) database, the AGA c.800dupT alteration was observed in 0.003% (7/251484) of total alleles studied, with a frequency of 0.02% (6/34592) in the Latino subpopulation. This alteration has been detected in a homozygous state in an individual with aspartylglucosaminidase, which was diagnosed via clinical features, detection of urinary glycoasparagines, and decreased AGA activity (Ikonen, 1991). This amino acid position is highly conserved in available vertebrate species. Based on the available evidence, this alteration is classified as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 06, 2024

Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 11309371); Frameshift variant predicted to result in abnormal protein length as the last 79 amino acids are replaced with 51 different amino acids, and other similar variants have been reported in HGMD; Also known as c.800_801insT; This variant is associated with the following publications: (PMID: 1722323, 11309371) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over