rs281865029
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_024312.5(GNPTAB):c.2574_2575del(p.Asn859GlnfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
GNPTAB
NM_024312.5 frameshift
NM_024312.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.140
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 12-101764341-TTC-T is Pathogenic according to our data. Variant chr12-101764341-TTC-T is described in ClinVar as [Pathogenic]. Clinvar id is 2769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-101764341-TTC-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GNPTAB | NM_024312.5 | c.2574_2575del | p.Asn859GlnfsTer2 | frameshift_variant | 13/21 | ENST00000299314.12 | |
GNPTAB | XM_006719593.4 | c.2574_2575del | p.Asn859GlnfsTer2 | frameshift_variant | 13/19 | ||
GNPTAB | XM_011538731.3 | c.2493_2494del | p.Asn832GlnfsTer2 | frameshift_variant | 13/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GNPTAB | ENST00000299314.12 | c.2574_2575del | p.Asn859GlnfsTer2 | frameshift_variant | 13/21 | 1 | NM_024312.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152252Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251302Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135828
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461790Hom.: 0 AF XY: 0.00000550 AC XY: 4AN XY: 727200
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Pseudo-Hurler polydystrophy Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2005 | - - |
Pathogenic, no assertion criteria provided | curation | GeneReviews | May 10, 2012 | - - |
Pseudo-Hurler polydystrophy;C2673377:Mucolipidosis type II Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 01, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | This sequence change creates a premature translational stop signal (p.Asn859Glnfs*2) 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). This variant is present in population databases (rs281865029, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with mucolipdosis III alpha (PMID: 16116615). This variant is also known as c.2574_2575delGA (p.E858fsX3). ClinVar contains an entry for this variant (Variation ID: 2769). For these reasons, this variant has been classified as Pathogenic. - |
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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