chrX-149487080-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000202.8(IDS):​c.1025A>C​(p.His342Pro) variant causes a missense change involving the alteration of a 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 Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 22)

Consequence

IDS
NM_000202.8 missense

Scores

10
6
1

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 7.57
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.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.979
PP5
Variant X-149487080-T-G is Pathogenic according to our data. Variant chrX-149487080-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 221972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-149487080-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
IDSNM_000202.8 linkc.1025A>C p.His342Pro missense_variant Exon 8 of 9 ENST00000340855.11 NP_000193.1 P22304-1
IDSNM_001166550.4 linkc.755A>C p.His252Pro missense_variant Exon 8 of 9 NP_001160022.1 P22304B4DGD7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
IDSENST00000340855.11 linkc.1025A>C p.His342Pro missense_variant Exon 8 of 9 1 NM_000202.8 ENSP00000339801.6 P22304-1
ENSG00000241489ENST00000651111.1 linkc.392A>C p.His131Pro missense_variant Exon 13 of 14 ENSP00000498395.1 B3KWA1
ENSG00000241489ENST00000422081.6 linkc.392A>C p.His131Pro missense_variant Exon 8 of 9 2 ENSP00000477056.1 B3KWA1
ENSG00000241489ENST00000441880.1 linkn.132A>C non_coding_transcript_exon_variant Exon 2 of 3 2

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
22

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-II Pathogenic:2
Likely pathogenic, criteria provided, single submitterresearchMOLECULAR BIOLOGY LABORATORY, INSTITUTO NACIONAL DE PEDIATRIAOct 18, 2015Likely pathogenic variation identified in a Hunter syndrome male patient without I2S evaluation. He presents mental retardation, but no seizures, nor hydrocephaly. Pathogenicity clues: Highly conserved nucleotide (phyloP: 0.96 [-5.2;1.1]); Highly conserved amino acid, up to Fruitfly (considering 12 species); Moderate physicochemical difference between His and Pro (Grantham dist.: 77 [0-215]); This variant is in protein domains: Sulfatase, Alkaline-phosphatase-like, core domain, Align GVGD: C0 (GV: 353.86 - GD: 0.00); SIFT: Deleterious (score: 0, median: 3.50); MutationTaster: disease causing (p-value: 1); PolyPhen prediction: Probably Damaging (score 1.0) -
Likely pathogenic, criteria provided, single submitterliterature onlyLaboratory of Diagnosis and Therapy of Lysosomal Disorders, University of PadovaJun 07, 2024Prevalence 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), 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
0.98
BayesDel_addAF
Pathogenic
0.71
D
BayesDel_noAF
Pathogenic
0.78
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.94
D;.
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Pathogenic
0.98
D
MetaRNN
Pathogenic
0.98
D;D
MetaSVM
Pathogenic
0.88
D
MutationAssessor
Pathogenic
3.1
M;.
PrimateAI
Uncertain
0.69
T
PROVEAN
Pathogenic
-9.2
D;.
REVEL
Pathogenic
0.97
Sift
Uncertain
0.0010
D;.
Sift4G
Uncertain
0.0050
D;D
Polyphen
1.0
D;.
Vest4
0.90
MutPred
0.81
Gain of ubiquitination at K347 (P = 0.0817);.;
MVP
1.0
MPC
1.0
ClinPred
1.0
D
GERP RS
5.3
Varity_R
0.98
gMVP
0.99

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: rs869025303; hg19: chrX-148568611; API