rs398123429
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The ENST00000268695.10(GALNS):āc.1171A>Gā(p.Met391Val) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,613,224 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 (ā ā ).
Frequency
Genomes: š 0.000020 ( 0 hom., cov: 33)
Exomes š: 0.000012 ( 0 hom. )
Consequence
GALNS
ENST00000268695.10 missense
ENST00000268695.10 missense
Scores
5
6
8
Clinical Significance
Conservation
PhyloP100: 5.74
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 16 ACMG points.
PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in ENST00000268695.10
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.98
PP5
Variant 16-88824838-T-C is Pathogenic according to our data. Variant chr16-88824838-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 93162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GALNS | NM_000512.5 | c.1171A>G | p.Met391Val | missense_variant | 11/14 | ENST00000268695.10 | NP_000503.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GALNS | ENST00000268695.10 | c.1171A>G | p.Met391Val | missense_variant | 11/14 | 1 | NM_000512.5 | ENSP00000268695 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152164Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000801 AC: 2AN: 249748Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135442
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GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461060Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11AN XY: 726808
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152164Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74306
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Mucopolysaccharidosis, MPS-IV-A Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 23, 2023 | This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 391 of the GALNS protein (p.Met391Val). This variant is present in population databases (rs398123429, gnomAD 0.002%). This missense change has been observed in individual(s) with mucopolysaccharidosis IVA (PMID: 7668283, 9375852, 25137622). ClinVar contains an entry for this variant (Variation ID: 93162). 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. Experimental studies have shown that this missense change affects GALNS function (PMID: 9375852). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | research | Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova | Feb 01, 2021 | In vitro and in vivo functional studies supportive of a damaging effect on the gene product (low to null in vitro enzymatic activity; low to null enzymatic activity in homozygotes; PS3_strong); 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) - |
Morquio syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 15, 2020 | Variant summary: GALNS c.1171A>G (p.Met391Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 249748 control chromosomes. c.1171A>G has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (example, Tomatsu_1995, Morrone_2014, Dung_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity in a transient expression system (Tomatsu_1995). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 although one submitter has classified the variant as pathogenic before 2014. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 13, 2013 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Benign
DEOGEN2
Uncertain
D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Pathogenic
Sift
Benign
T
Sift4G
Benign
T
Polyphen
P
Vest4
MutPred
Gain of sheet (P = 0.0344);
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