rs121434533
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate
The NM_000262.3(NAGA):c.986G>A(p.Arg329Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000409 in 1,614,178 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R329W) has been classified as Pathogenic.
Frequency
Consequence
NM_000262.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NAGA | NM_000262.3 | c.986G>A | p.Arg329Gln | missense_variant | 8/9 | ENST00000396398.8 | |
NAGA | NM_001362848.1 | c.986G>A | p.Arg329Gln | missense_variant | 9/10 | ||
NAGA | NM_001362850.1 | c.986G>A | p.Arg329Gln | missense_variant | 9/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NAGA | ENST00000396398.8 | c.986G>A | p.Arg329Gln | missense_variant | 8/9 | 1 | NM_000262.3 | P1 | |
NAGA | ENST00000402937.1 | c.986G>A | p.Arg329Gln | missense_variant | 9/10 | 5 | P1 | ||
NAGA | ENST00000403363.5 | c.986G>A | p.Arg329Gln | missense_variant | 9/10 | 5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152194Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000676 AC: 17AN: 251438Hom.: 0 AF XY: 0.0000957 AC XY: 13AN XY: 135900
GnomAD4 exome AF: 0.0000397 AC: 58AN: 1461866Hom.: 0 Cov.: 32 AF XY: 0.0000536 AC XY: 39AN XY: 727236
GnomAD4 genome AF: 0.0000525 AC: 8AN: 152312Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6AN XY: 74466
ClinVar
Submissions by phenotype
Alpha-N-acetylgalactosaminidase deficiency type 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2001 | - - |
NAGA-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 30, 2018 | The NAGA c.986G>A (p.Arg329Gln) missense variant has been reported in a homozygous state in one individual with Kanzaki disease (Kodama et al. 2001). The α-N-acetylgalactosaminidase enzyme activity in the individual's plasma was 0.77% of normal. Further evaluation of this individual showed that the ratio of urinary excreted GalNAcα1-O-Ser to GalNAcα1-O-Thr was 2:10, indicating that the p.Arg329Gln variant retains some ability to catalyze GalNAcα1-O-Ser (Kanekura et al. 2005). Homology modeling suggests that the p.Arg329Gln variant disrupts hydrogen bonds at the interface between domains I and II, which decreases protein stability and may cause a folding defect (Sakuraba et al. 2004). Control data are unavailable for this variant, which is reported at a frequency of 0.00006 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Arg329Gln is classified as a variant of unknown significance but suspicious for pathogenicity for NAGA-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at