rs864622772
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000202.8(IDS):c.1393C>T(p.Gln465Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q465Q) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 23)
Consequence
IDS
NM_000202.8 stop_gained
NM_000202.8 stop_gained
Scores
2
2
1
Clinical Significance
Conservation
PhyloP100: 6.79
Genes affected
IDS (HGNC:5389): (iduronate 2-sulfatase) This gene encodes a member of the sulfatase family of proteins. The encoded preproprotein is proteolytically processed to generate two polypeptide chains. This enzyme is involved in the lysosomal degradation of heparan sulfate and dermatan sulfate. Mutations in this gene are associated with the X-linked lysosomal storage disease mucopolysaccharidosis type II, also known as Hunter syndrome. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. [provided by RefSeq, Jan 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 93 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant X-149483006-G-A is Pathogenic according to our data. Variant chrX-149483006-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 221202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-149483006-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IDS | NM_000202.8 | c.1393C>T | p.Gln465Ter | stop_gained | 9/9 | ENST00000340855.11 | |
IDS | NM_001166550.4 | c.1123C>T | p.Gln375Ter | stop_gained | 9/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IDS | ENST00000340855.11 | c.1393C>T | p.Gln465Ter | stop_gained | 9/9 | 1 | NM_000202.8 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Mucopolysaccharidosis, MPS-II Pathogenic:4
Pathogenic, criteria provided, single submitter | research | IIFP, CONICET-UNLP | Oct 30, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 19, 2018 | This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with mucopolysaccharidosis type II (PMID: 8830188, 17063374, Invitae). ClinVar contains an entry for this variant (Variation ID: 221202). Other truncations (p.Met488Serfs*11, p.Tyr523Leufs*6 and p.Leu530Phefs*8) that lie downstream of this variant have been reported in individuals affected with mucopolysaccharidosis type II (PMID: 27246110, 8940265, 17284421). For these reasons, this variant has been classified as Pathogenic. This sequence change results in a premature translational stop signal in the IDS gene (p.Gln465*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 86 amino acids of the IDS protein. - |
Pathogenic, criteria provided, single submitter | literature only | Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova | Jun 07, 2024 | Null variant (PVS1_Strong), Prevalence of the variant significantly increased in affected individuals compared with controls (PS4_Supporting), Absent from controls (or at low frequency) in gnomAD database (PM2_Moderate), Patient’s phenotype or family history highly specific for the disease (PP4_Strong) - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 16, 2022 | Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 85 amino acids are lost, and other variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25681085, 17063374, 9950361, 8830188, 27896113) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D;D
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at