rs386833431
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1_StrongPM2PP3_StrongPP5_Very_Strong
The ENST00000510635.1(AGA):c.372+1G>A variant causes a splice donor change. The variant allele was found at a frequency of 0.0000198 in 1,612,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000019 ( 0 hom. )
Consequence
AGA
ENST00000510635.1 splice_donor
ENST00000510635.1 splice_donor
Scores
14
4
1
Clinical Significance
Conservation
PhyloP100: 7.01
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.12801932 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.2, offset of -15, new splice context is: ctgGTacat. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.996
PP5
?
Variant 4-177436297-C-T is Pathogenic according to our data. Variant chr4-177436297-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-177436297-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AGA | NM_000027.4 | c.677G>A | p.Gly226Asp | missense_variant | 6/9 | ENST00000264595.7 | |
AGA | NM_001171988.2 | c.676+1G>A | splice_donor_variant | ||||
AGA | XM_047449722.1 | c.676+1G>A | splice_donor_variant | ||||
AGA | NR_033655.2 | n.684+1108G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AGA | ENST00000510635.1 | c.372+1G>A | splice_donor_variant | 1 | |||||
AGA | ENST00000264595.7 | c.677G>A | p.Gly226Asp | missense_variant | 6/9 | 1 | NM_000027.4 | P1 | |
AGA | ENST00000502310.5 | c.277+1108G>A | intron_variant | 5 | |||||
AGA | ENST00000506853.5 | n.656+1108G>A | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 151918Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251294Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135860
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GnomAD4 exome AF: 0.0000192 AC: 28AN: 1460902Hom.: 0 Cov.: 30 AF XY: 0.0000261 AC XY: 19AN XY: 726838
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 151918Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74172
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Aspartylglucosaminuria Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 09, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 226 of the AGA protein (p.Gly226Asp). RNA analysis indicates that this missense change induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs386833431, gnomAD 0.002%). This missense change has been observed in individual(s) with AGA-related conditions (PMID: 10399108, 29930972). ClinVar contains an entry for this variant (Variation ID: 55950). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt AGA protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects AGA function (PMID: 11309371, 18992224). Studies have shown that this missense change results in skipping of exon 6 and introduces a new termination codon (PMID: 10399108, 11309371). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jan 22, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 22, 2021 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 26, 2022 | Published functional studies demonstrate a damaging effect of significantly reduced enzyme activity (Sui et al., 2014; Saarela et al., 2001); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18992224, 25525159, 10399108, 11309371, 14616088, 28457719, 25456816) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Loss of methylation at K228 (P = 0.0598);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at