rs193302907

Variant names:

• chrX-149496405-C-A
• rs193302907
• NM_000202.8:c.820G>T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000202.8(IDS):​c.820G>T​(p.Glu274*) variant causes a stop gained 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 24)
• Consequence: IDS NM_000202.8 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.47
• 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 2

  Inheritance: 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 form

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• mucopolysaccharidosis type 2, severe form

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000241489 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 20 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
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-149496405-C-A is Pathogenic according to our data. Variant chrX-149496405-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 221214.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
IDS	NM_000202.8	c.820G>T	p.Glu274*	stop_gained	Exon 6 of 9	ENST00000340855.11	NP_000193.1
IDS	NM_001166550.4	c.550G>T	p.Glu184*	stop_gained	Exon 6 of 9		NP_001160022.1
IDS	NM_006123.5	c.820G>T	p.Glu274*	stop_gained	Exon 6 of 8		NP_006114.1
IDS	NR_104128.2	n.989G>T		non_coding_transcript_exon_variant	Exon 6 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDS	ENST00000340855.11	c.820G>T	p.Glu274*	stop_gained	Exon 6 of 9	1	NM_000202.8	ENSP00000339801.6
ENSG00000241489	ENST00000651111.1	c.187G>T	p.Glu63*	stop_gained	Exon 11 of 14			ENSP00000498395.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-II Pathogenic:2

May 27, 2010

IIFP, CONICET-UNLP

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

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

Null variant (PVS1_VeryStrong), Absent from controls (or at low frequency) in gnomAD database (PM2_Moderate), Patient’s phenotype or family history highly specific for the disease (PP4_Moderate) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	48
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		7.5
Vest4		0.94
GERP RS		5.4
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.99		Position offset: 2

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

Other links and lift over

dbSNP: rs193302907; hg19: chrX-148577936;