X-149504264-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1_ModeratePM1PM2PM5PP3_StrongPP5_Moderate

The NM_000202.8(IDS):​c.133G>A​(p.Asp45Asn) variant causes a missense 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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D45G) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 23)

Consequence

IDS
NM_000202.8 missense

Scores

13
3
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.06
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 14 ACMG points.

PS1
Transcript NM_000202.8 (IDS) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM1
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000202.8
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrX-149504263-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2498324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.989
PP5
Variant X-149504264-C-T is Pathogenic according to our data. Variant chrX-149504264-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3255838.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-149504264-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
IDSNM_000202.8 linkuse as main transcriptc.133G>A p.Asp45Asn missense_variant 2/9 ENST00000340855.11
IDSNM_006123.5 linkuse as main transcriptc.133G>A p.Asp45Asn missense_variant 2/8
IDSNM_001166550.4 linkuse as main transcriptc.-94G>A 5_prime_UTR_variant 2/9
IDSNR_104128.2 linkuse as main transcriptn.302G>A non_coding_transcript_exon_variant 2/9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
IDSENST00000340855.11 linkuse as main transcriptc.133G>A p.Asp45Asn missense_variant 2/91 NM_000202.8 P1P22304-1

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-II Pathogenic:1
Pathogenic, criteria provided, single submitterliterature onlyLaboratory of Diagnosis and Therapy of Lysosomal Disorders, University of PadovaJun 07, 2024Located in a mutational hot spot and/or critical functional domain (PM1_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) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.21
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.98
D;.;D;.
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Pathogenic
0.98
D;D;D;D
M_CAP
Pathogenic
0.96
D
MetaRNN
Pathogenic
0.99
D;D;D;D
MetaSVM
Pathogenic
0.91
D
MutationAssessor
Pathogenic
4.4
H;H;.;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Uncertain
0.65
T
PROVEAN
Uncertain
-4.2
D;D;D;D
REVEL
Pathogenic
0.93
Sift
Pathogenic
0.0
D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;.
Polyphen
1.0
D;D;D;.
Vest4
0.99
MutPred
0.97
Gain of methylation at R48 (P = 0.1859);Gain of methylation at R48 (P = 0.1859);Gain of methylation at R48 (P = 0.1859);Gain of methylation at R48 (P = 0.1859);
MVP
1.0
MPC
2.2
ClinPred
1.0
D
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6
Varity_R
0.98
gMVP
1.0

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-148585794; API