rs281864982
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_024312.5(GNPTAB):c.1759C>T(p.Arg587Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000274 in 1,461,838 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
GNPTAB
NM_024312.5 stop_gained
NM_024312.5 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 6.19
Genes affected
GNPTAB (HGNC:29670): (N-acetylglucosamine-1-phosphate transferase subunits alpha and beta) This gene encodes two of three subunit types of the membrane-bound enzyme N-acetylglucosamine-1-phosphotransferase, a heterohexameric complex composed of two alpha, two beta, and two gamma subunits. The encoded protein is proteolytically cleaved at the Lys928-Asp929 bond to yield mature alpha and beta polypeptides while the gamma subunits are the product of a distinct gene (GeneID 84572). In the Golgi apparatus, the heterohexameric complex catalyzes the first step in the synthesis of mannose 6-phosphate recognition markers on certain oligosaccharides of newly synthesized lysosomal enzymes. These recognition markers are essential for appropriate trafficking of lysosomal enzymes. Mutations in this gene have been associated with both mucolipidosis II and mucolipidosis IIIA.[provided by RefSeq, May 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 12-101765158-G-A is Pathogenic according to our data. Variant chr12-101765158-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 39040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101765158-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GNPTAB | NM_024312.5 | c.1759C>T | p.Arg587Ter | stop_gained | 13/21 | ENST00000299314.12 | |
GNPTAB | XM_011538731.3 | c.1678C>T | p.Arg560Ter | stop_gained | 13/21 | ||
GNPTAB | XM_006719593.4 | c.1759C>T | p.Arg587Ter | stop_gained | 13/19 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GNPTAB | ENST00000299314.12 | c.1759C>T | p.Arg587Ter | stop_gained | 13/21 | 1 | NM_024312.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461838Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727216
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GnomAD4 genome ? Cov.: 33
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Pseudo-Hurler polydystrophy;C2673377:Mucolipidosis type II Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 13, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 28, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 39040). This premature translational stop signal has been observed in individuals with mucolipidosis types II and III (PMID: 19617216, 23566849). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg587*) in the GNPTAB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GNPTAB are known to be pathogenic (PMID: 19617216, 25107912). - |
Mucolipidosis type II Pathogenic:1Other:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jun 30, 2020 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Mucolipidosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 15, 2021 | Variant summary: GNPTAB c.1759C>T (p.Arg587X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251420 control chromosomes. c.1759C>T has been reported in the literature in individuals affected with Mucolipidosis (example, Cathey_2010, Cury_2013, Velho_2015). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <2% of normal GlcNAc-1- phosphotransferase enzyme activity in HEK-293 cells overexpressing full-length WT or mutant /-subunit constructs (Velho_2015). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
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
Pathogenic
D
MutationTaster
Benign
A
Vest4
GERP RS
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