X-149498202-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_000202.8(IDS):​c.613G>A​(p.Ala205Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000273 in 1,097,556 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 24)
Exomes 𝑓: 0.0000027 ( 0 hom. 0 hem. )

Consequence

IDS
NM_000202.8 missense

Scores

8
7
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 7.34
Variant links:
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 12 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.868
PP5
Variant X-149498202-C-T is Pathogenic according to our data. Variant chrX-149498202-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 816852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
IDSNM_000202.8 linkc.613G>A p.Ala205Thr missense_variant Exon 5 of 9 ENST00000340855.11 NP_000193.1 P22304-1
IDSNM_001166550.4 linkc.343G>A p.Ala115Thr missense_variant Exon 5 of 9 NP_001160022.1 P22304B4DGD7
IDSNM_006123.5 linkc.613G>A p.Ala205Thr missense_variant Exon 5 of 8 NP_006114.1 P22304-2
IDSNR_104128.2 linkn.782G>A non_coding_transcript_exon_variant Exon 5 of 9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
IDSENST00000340855.11 linkc.613G>A p.Ala205Thr missense_variant Exon 5 of 9 1 NM_000202.8 ENSP00000339801.6 P22304-1
ENSG00000241489ENST00000651111.1 linkc.-21G>A 5_prime_UTR_variant Exon 10 of 14 ENSP00000498395.1 B3KWA1

Frequencies

GnomAD3 genomes
Cov.:
24
GnomAD4 exome
AF:
0.00000273
AC:
3
AN:
1097556
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
362912
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000247
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000434
GnomAD4 genome
Cov.:
24

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-II Pathogenic:3
Jun 07, 2024
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: literature only

Prevalence of the variant significantly increased in affected individuals compared with controls (PS4_Moderate), Absent from controls (or at low frequency) in gnomAD database (PM2_Moderate), Missense variant in a gene with a low rate of benign missense variation (PP2_Supporting), Multiple lines of computational evidence support a deleterious effect (PP3_Supporting), Patient’s phenotype or family history highly specific for the disease (PP4_Strong) -

Feb 16, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.31
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.43
CADD
Pathogenic
26
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.93
D;.
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.92
D;D
M_CAP
Pathogenic
0.69
D
MetaRNN
Pathogenic
0.87
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.4
M;M
PrimateAI
Uncertain
0.58
T
PROVEAN
Uncertain
-3.5
D;D
REVEL
Pathogenic
0.86
Sift
Uncertain
0.0020
D;D
Sift4G
Uncertain
0.0030
D;D
Polyphen
1.0
D;D
Vest4
0.86
MutPred
0.51
Gain of loop (P = 0.0079);Gain of loop (P = 0.0079);
MVP
0.96
MPC
0.77
ClinPred
0.99
D
GERP RS
5.1
Varity_R
0.96
gMVP
0.96

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs864622779; hg19: chrX-148579733; API