rs761385192
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Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000512.5(GALNS):c.740G>A(p.Gly247Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,613,984 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000040 ( 0 hom. )
Consequence
GALNS
NM_000512.5 missense
NM_000512.5 missense
Scores
9
5
5
Clinical Significance
Conservation
PhyloP100: 7.53
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 Likely_pathogenic. Variant got 9 ACMG points.
PM1
?
In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000512.5
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.963
PP5
?
Variant 16-88835743-C-T is Pathogenic according to our data. Variant chr16-88835743-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 198426.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Pathogenic=2, Likely_benign=1}. Variant chr16-88835743-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GALNS | NM_000512.5 | c.740G>A | p.Gly247Asp | missense_variant | 7/14 | ENST00000268695.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GALNS | ENST00000268695.10 | c.740G>A | p.Gly247Asp | missense_variant | 7/14 | 1 | NM_000512.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000328 AC: 5AN: 152244Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251280Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135852
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GnomAD4 exome AF: 0.0000404 AC: 59AN: 1461740Hom.: 0 Cov.: 32 AF XY: 0.0000495 AC XY: 36AN XY: 727170
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GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152244Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74378
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:5Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Mucopolysaccharidosis, MPS-IV-A Pathogenic:2Benign:1
Likely pathogenic, criteria provided, single submitter | research | Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova | Feb 01, 2021 | In vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; 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); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 29, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 247 of the GALNS protein (p.Gly247Asp). This variant is present in population databases (rs761385192, gnomAD 0.005%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IVA (PMID: 9298823, 15235041, 23876334). ClinVar contains an entry for this variant (Variation ID: 198426). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GALNS protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 02, 2021 | We found this variant in a 40-year-old asymptomatic female in a homozygous state. - |
Morquio syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 26, 2023 | Variant summary: GALNS c.740G>A (p.Gly247Asp) results in a non-conservative amino acid change located in the Sulfatase, N-terminal (IRP000917) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251280 control chromosomes (gnomAD). c.740G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A, Bhattacharya_2014, Bunge_1997, Dung_2013, Tomatsu_2004), and some were reported as compound heterozygous with likely pathogenic variants. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 23876334, 15235041, 9298823, 25433535). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic/likely pathogenic (n=4) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 18, 2018 | VARIANT INTERPRETATION: The p.Gly247Asp (NM_000512.4 c.740G>A) variant in GALNS has been reported in at least 5 compound heterozygous patients with mucopolysacc haridosis type IVa (Bunge 1997, Tomatsu 2004, Bhattacharya 2014, and Morrone 201 4). This variant has also been identified in 6/126,672 of European chromosomes b y the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbS NP rs761385192). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, the p.Gly247 Asp variant is likely pathogenic for mucopolysaccaridosis type IVa in an autosom al recessive manner based on its occurrence in affected individuals. ACMG/AMP Cr iteria applied: PM2, PM3 (upgraded to Strong based on multiple occurrences) (Ric hards 2015). - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 22, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Benign
T
Sift4G
Benign
T
Polyphen
P
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
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