16-88841083-G-A
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000512.5(GALNS):c.331C>T(p.Gln111Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000391 in 1,612,914 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: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000040 ( 0 hom. )
Consequence
GALNS
NM_000512.5 stop_gained
NM_000512.5 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 9.91
Genes affected
GALNS (HGNC:4122): (galactosamine (N-acetyl)-6-sulfatase) This gene encodes N-acetylgalactosamine-6-sulfatase which is a lysosomal exohydrolase required for the degradation of the glycosaminoglycans, keratan sulfate, and chondroitin 6-sulfate. Sequence alterations including point, missense and nonsense mutations, as well as those that affect splicing, result in a deficiency of this enzyme. Deficiencies of this enzyme lead to Morquio A syndrome, a lysosomal storage disorder. [provided by RefSeq, Jul 2008]
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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 16-88841083-G-A is Pathogenic according to our data. Variant chr16-88841083-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 569803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GALNS | NM_000512.5 | c.331C>T | p.Gln111Ter | stop_gained | 4/14 | ENST00000268695.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GALNS | ENST00000268695.10 | c.331C>T | p.Gln111Ter | stop_gained | 4/14 | 1 | NM_000512.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152178Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250768Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135842
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GnomAD4 exome AF: 0.0000404 AC: 59AN: 1460736Hom.: 0 Cov.: 31 AF XY: 0.0000317 AC XY: 23AN XY: 726692
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152178Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74346
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Mucopolysaccharidosis, MPS-IV-A Pathogenic:3
Pathogenic, criteria provided, single submitter | research | Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova | Feb 01, 2021 | Nonsense variant (PVS1_very strong); in vitro functional studies supportive of a damaging effect on the gene product (low in vitro enzymatic activity; PS3_supporting); the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_strong); very low frequency in gnomAD v2.1.1 (PM2_moderate) - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 09, 2023 | This sequence change creates a premature translational stop signal (p.Gln111*) in the GALNS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GALNS are known to be pathogenic (PMID: 12442278). This variant is present in population databases (rs200374326, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with mucopolysaccharidosis type IV (PMID: 9375852). ClinVar contains an entry for this variant (Variation ID: 569803). For these reasons, this variant has been classified as Pathogenic. - |
Morquio syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 27, 2020 | Variant summary: GALNS c.331C>T (p.Gln111X) 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 1.6e-05 in 250768 control chromosomes. c.331C>T has been reported in the literature in individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) and subsequently cited by others (example, Tomatsu_2005, Morrone_2014). These data indicate that the variant is very likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
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Name
Calibrated prediction
Score
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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