rs761987059
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_024312.5(GNPTAB):βc.344_345delβ(p.Thr115AsnfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000115 in 1,567,654 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. T115T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_024312.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GNPTAB | NM_024312.5 | c.344_345del | p.Thr115AsnfsTer5 | frameshift_variant | 4/21 | ENST00000299314.12 | |
GNPTAB | XM_006719593.4 | c.344_345del | p.Thr115AsnfsTer5 | frameshift_variant | 4/19 | ||
GNPTAB | XM_011538731.3 | c.263_264del | p.Thr88AsnfsTer5 | frameshift_variant | 4/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GNPTAB | ENST00000299314.12 | c.344_345del | p.Thr115AsnfsTer5 | frameshift_variant | 4/21 | 1 | NM_024312.5 | P1 | |
GNPTAB | ENST00000549940.5 | c.344_345del | p.Thr115AsnfsTer5 | frameshift_variant | 4/11 | 1 | |||
GNPTAB | ENST00000550352.1 | n.138_139del | non_coding_transcript_exon_variant | 2/3 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152248Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000478 AC: 12AN: 251084Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135724
GnomAD4 exome AF: 0.0000106 AC: 15AN: 1415406Hom.: 0 AF XY: 0.0000113 AC XY: 8AN XY: 707264
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152248Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74380
ClinVar
Submissions by phenotype
Pseudo-Hurler polydystrophy;C2673377:Mucolipidosis type II Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 13, 2023 | This sequence change creates a premature translational stop signal (p.Thr115Asnfs*5) 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 (rs761987059, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with mucolipidosis (PMID: 19617216). ClinVar contains an entry for this variant (Variation ID: 39073). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 15, 2018 | - - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 12, 2023 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24127423, 19617216, 30882951, 32182687, 25601403) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 02, 2016 | - - |
Mucolipidosis type II Pathogenic:1Other:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 16, 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 | Aug 07, 2020 | Variant summary: GNPTAB c.344_345delCA (p.Thr115AsnfsX5) 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 allele was found at a frequency of 4.8e-05 in 251084 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in GNPTAB causing Mucolipidosis (4.8e-05 vs 0.0022), allowing no conclusion about variant significance. c.344_345delCA has been reported in the literature in multiple individuals in compound heterozygous and homozygous states affected with Mucolipidosis II (Cathey_2010, Kollmann_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at