rs199422230

chrX-149482974-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000202.8(IDS):c.1425G>A(p.Trp475Ter) variant causes a stop gained 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 (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: IDS NM_000202.8 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.07

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 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 36 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-149482974-C-T is Pathogenic according to our data. Variant chrX-149482974-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 10495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-149482974-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDS	NM_000202.8	c.1425G>A	p.Trp475Ter	stop_gained	9/9	ENST00000340855.11
IDS	NM_001166550.4	c.1155G>A	p.Trp385Ter	stop_gained	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDS	ENST00000340855.11	c.1425G>A	p.Trp475Ter	stop_gained	9/9	1	NM_000202.8	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-II Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 23, 2021	This variant disrupts a region of the IDS protein in which other variant(s) (p.Leu530Phefs*8) have been determined to be pathogenic (PMID: 7581397, 17284421; external communication). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 10495). This premature translational stop signal has been observed in individual(s) with Hunter syndrome (PMID: 1303211). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp475*) in the IDS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 76 amino acid(s) of the IDS protein. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 1992	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	36
Dann	Uncertain	0.99
FATHMM_MKL	Uncertain	0.86	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.75
GERP RS		4.7

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

Other links and lift over

dbSNP: rs199422230; hg19: chrX-148564505;