X-149503478-G-T
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000202.8(IDS):c.252C>A(p.Cys84*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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. C84C) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 23)
Exomes 𝑓: 9.9e-7 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control
Consequence
IDS
NM_000202.8 stop_gained
NM_000202.8 stop_gained
Scores
2
1
1
Clinical Significance
Conservation
PhyloP100: -0.0810
Publications
1 publications found
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]
IDS Gene-Disease associations (from GenCC):
- mucopolysaccharidosis type 2Inheritance: XL, AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, PanelApp Australia, Myriad Women’s Health
- mucopolysaccharidosis type 2, attenuated formInheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
- mucopolysaccharidosis type 2, severe formInheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 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 X-149503478-G-T is Pathogenic according to our data. Variant chrX-149503478-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 502523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000202.8. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| IDS | NM_000202.8 | MANE Select | c.252C>A | p.Cys84* | stop_gained | Exon 3 of 9 | NP_000193.1 | ||
| IDS | NM_006123.5 | c.252C>A | p.Cys84* | stop_gained | Exon 3 of 8 | NP_006114.1 | |||
| IDS | NM_001166550.4 | c.15-33C>A | intron | N/A | NP_001160022.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| IDS | ENST00000340855.11 | TSL:1 MANE Select | c.252C>A | p.Cys84* | stop_gained | Exon 3 of 9 | ENSP00000339801.6 | ||
| IDS | ENST00000370441.8 | TSL:1 | c.252C>A | p.Cys84* | stop_gained | Exon 3 of 8 | ENSP00000359470.4 | ||
| ENSG00000241489 | ENST00000651111.1 | c.-215-2441C>A | intron | N/A | ENSP00000498395.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
23
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.87e-7 AC: 1AN: 1013542Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0AN XY: 303520 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
1
AN:
1013542
Hom.:
Cov.:
23
AF XY:
AC XY:
0
AN XY:
303520
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
24814
American (AMR)
AF:
AC:
0
AN:
29082
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
18446
East Asian (EAS)
AF:
AC:
0
AN:
28873
South Asian (SAS)
AF:
AC:
0
AN:
49764
European-Finnish (FIN)
AF:
AC:
0
AN:
38713
Middle Eastern (MID)
AF:
AC:
0
AN:
3099
European-Non Finnish (NFE)
AF:
AC:
1
AN:
777478
Other (OTH)
AF:
AC:
0
AN:
43273
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.325
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
GnomAD4 genome
Cov.:
23
ClinVar
ClinVar submissions as Germline
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
1
-
-
Mucopolysaccharidosis, MPS-II (1)
1
-
-
not provided (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
DANN
Uncertain
FATHMM_MKL
Benign
N
PhyloP100
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
Publications
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