rs1060499690
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_032520.5(GNPTG):c.324G>A(p.Trp108Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Consequence
GNPTG
NM_032520.5 stop_gained
NM_032520.5 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 9.22
Genes affected
GNPTG (HGNC:23026): (N-acetylglucosamine-1-phosphate transferase subunit gamma) This gene encodes the gamma sunbunit of the N-acetylglucosamine-1-phosphotransferase complex. This hexameric complex, composed of alpha, beta and gamma subunits, catalyzes the first step in synthesis of a mannose 6-phosphate lysosomal recognition marker. This enzyme complex is necessary for targeting of lysosomal hydrolases to the lysosome. Mutations in the gene encoding the gamma subunit have been associated with mucolipidosis IIIC, also known as mucolipidosis III gamma.[provided by RefSeq, Feb 2010]
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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 16-1362044-G-A is Pathogenic according to our data. Variant chr16-1362044-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 397575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1362044-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GNPTG | NM_032520.5 | c.324G>A | p.Trp108Ter | stop_gained | 6/11 | ENST00000204679.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GNPTG | ENST00000204679.9 | c.324G>A | p.Trp108Ter | stop_gained | 6/11 | 1 | NM_032520.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
GNPTG-mucolipidosis Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS | Jan 01, 2016 | - - |
Mucolipidosis Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 02, 2018 | The p.Trp108X variant in GNPTG has not been previously reported in the literatur e and was absent from large population studies, but has been reported in ClinVar (Variation ID #397575). This nonsense variant leads to a premature termination codon at position 108 which is predicted to lead to a truncated or absent protei n. Loss of function is a reported mechanism of disease for this gene. In summary , although additional studies are required to fully establish its clinical signi ficance, the p.Trp108X variant is likely pathogenic for Mucolipidosis III gamma based on predicted impact on protein and absence from the general population. AC MG/AMP Criteria applied: PM2, PVS1 - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A
Vest4
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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