rs281865000
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_024312.5(GNPTAB):c.2693del(p.Lys898SerfsTer13) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000041 in 1,461,648 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
GNPTAB
NM_024312.5 frameshift
NM_024312.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.37
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 12-101764223-CT-C is Pathogenic according to our data. Variant chr12-101764223-CT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 39058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101764223-CT-C is described in Lovd as [Pathogenic]. Variant chr12-101764223-CT-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GNPTAB | NM_024312.5 | c.2693del | p.Lys898SerfsTer13 | frameshift_variant | 13/21 | ENST00000299314.12 | |
GNPTAB | XM_011538731.3 | c.2612del | p.Lys871SerfsTer13 | frameshift_variant | 13/21 | ||
GNPTAB | XM_006719593.4 | c.2693del | p.Lys898SerfsTer13 | frameshift_variant | 13/19 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GNPTAB | ENST00000299314.12 | c.2693del | p.Lys898SerfsTer13 | frameshift_variant | 13/21 | 1 | NM_024312.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461648Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727132
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GnomAD4 genome Cov.: 32
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32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Pseudo-Hurler polydystrophy;C2673377:Mucolipidosis type II Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Apr 04, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 21, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 39058). This premature translational stop signal has been observed in individual(s) with mucolipidosis III (PMID: 19197337). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Lys898Serfs*13) 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). - |
Pseudo-Hurler polydystrophy Pathogenic:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 28, 2016 | Variant summary: The GNPTAB c.2693delA (p.Lys898Serfs) variant results in a premature termination codon, predicted to cause a truncated or absent GNPTAB protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was not found in controls (ExAC, 1000 Gs or ESP) and has been reported in one affected individual who was diagnosed with ML III and was compound heterozygous for the variant of interest and an exon 2 duplication. GeneReviews classifies the variant as "pathogenic." Therefore, taking all available lines of evidence into consideration the varinat of interest has been classified as Pathogenic. - |
Mucolipidosis Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Department of Genetics and Endocrinology, Guangzhou Women and Children’s Medical Center | - | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Kariminejad - Najmabadi Pathology & Genetics Center | Jul 10, 2021 | - - |
Computational scores
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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