rs121964907
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000027.4(AGA):c.179G>A(p.Gly60Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
AGA
NM_000027.4 missense
NM_000027.4 missense
Scores
14
4
1
Clinical Significance
Conservation
PhyloP100: 7.43
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 Likely_pathogenic. Variant got 9 ACMG points.
PM1
In a chain Glycosylasparaginase alpha chain (size 181) in uniprot entity ASPG_HUMAN there are 13 pathogenic changes around while only 5 benign (72%) in NM_000027.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.996
PP5
Variant 4-177440375-C-T is Pathogenic according to our data. Variant chr4-177440375-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 222.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=3}. Variant chr4-177440375-C-T is described in Lovd as [Likely_pathogenic]. Variant chr4-177440375-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
AGA | NM_000027.4 | c.179G>A | p.Gly60Asp | missense_variant | 2/9 | ENST00000264595.7 | NP_000018.2 | |
AGA | NM_001171988.2 | c.179G>A | p.Gly60Asp | missense_variant | 2/9 | NP_001165459.1 | ||
AGA | XM_047449722.1 | c.179G>A | p.Gly60Asp | missense_variant | 2/7 | XP_047305678.1 | ||
AGA | NR_033655.2 | n.241G>A | non_coding_transcript_exon_variant | 2/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
AGA | ENST00000264595.7 | c.179G>A | p.Gly60Asp | missense_variant | 2/9 | 1 | NM_000027.4 | ENSP00000264595.2 | ||
AGA | ENST00000506853.5 | n.213G>A | non_coding_transcript_exon_variant | 2/6 | 2 | |||||
AGA | ENST00000510955.5 | n.213G>A | non_coding_transcript_exon_variant | 2/4 | 2 | |||||
AGA | ENST00000511231.1 | n.213G>A | non_coding_transcript_exon_variant | 2/2 | 2 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461850Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727230
GnomAD4 exome
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1
AN:
1461850
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33
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1
AN XY:
727230
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GnomAD4 genome Cov.: 31
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Aspartylglucosaminuria Pathogenic:4Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 09, 2021 | ClinVar contains an entry for this variant (Variation ID: 222). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this variant affects AGA protein function (PMID: 11309371). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change replaces glycine with aspartic acid at codon 60 of the AGA protein (p.Gly60Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with aspartylglucosaminuria (PMID: 1722323). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 15, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 20, 2024 | Variant summary: AGA c.179G>A (p.Gly60Asp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251432 control chromosomes. c.179G>A has been reported in the literature as a homozygous genotype in at-least one individual affected with Aspartylglucosaminuria (Ikonen_1991). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in < 10% of normal fibroblast AGA activity in a homozygous individual. The following publications have been ascertained in the context of this evaluation (PMID: 1722323, 11309371). ClinVar contains an entry for this variant (Variation ID: 222). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 15, 1991 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 15, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Loss of glycosylation at S59 (P = 0.043);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at