rs199422229

Positions:

• chrX-149483135-A-C
• chrX-149483135-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The ENST00000340855.11(IDS):​c.1264T>G​(p.Cys422Gly) 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. C422F) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: IDS ENST00000340855.11 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 6.35

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-149483134-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 592185.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-149483135-A-C is Pathogenic according to our data. Variant chrX-149483135-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 10493.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-149483135-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDS	NM_000202.8	c.1264T>G	p.Cys422Gly	missense_variant	9/9	ENST00000340855.11	NP_000193.1
IDS	NM_001166550.4	c.994T>G	p.Cys332Gly	missense_variant	9/9		NP_001160022.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDS	ENST00000340855.11	c.1264T>G	p.Cys422Gly	missense_variant	9/9	1	NM_000202.8	ENSP00000339801	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Mucopolysaccharidosis, MPS-II Pathogenic:3

Likely pathogenic, no assertion criteria provided	research	Molecular Biology Laboratory, Department of Zoology, Quaid-i-azam University	-	- -
Pathogenic, criteria provided, single submitter	literature only	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	Jun 07, 2024	Located 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) -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 1992	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.74
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.80	D;.
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.5	M;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-11	D;.
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0050	D;.
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.48	P;.
Vest4		0.72
MutPred		0.92		Loss of stability (P = 0.0125);.;
MVP		1.0
MPC		0.88
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.95
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs199422229; hg19: chrX-148564666;