rs121964907
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The ENST00000264595.7(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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G60S) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000264595.7 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
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 | P1 | |
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
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461850Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727230
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Aspartylglucosaminuria Pathogenic:4Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 15, 1991 | - - |
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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 15, 2017 | - - |
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). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at