rs864622775

Positions:

• chrX-149505100-AGCCAGAGAAGGCCTCG-A

Variant summary

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

The ENST00000340855.11(IDS):​c.22_37del​(p.Arg8TrpfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R8R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: IDS ENST00000340855.11 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.74

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 located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 762 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-149505100-AGCCAGAGAAGGCCTCG-A is Pathogenic according to our data. Variant chrX-149505100-AGCCAGAGAAGGCCTCG-A is described in ClinVar as [Pathogenic]. Clinvar id is 221215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-149505100-AGCCAGAGAAGGCCTCG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDS	NM_000202.8	c.22_37del	p.Arg8TrpfsTer5	frameshift_variant	1/9	ENST00000340855.11	NP_000193.1
IDS	NM_006123.5	c.22_37del	p.Arg8TrpfsTer5	frameshift_variant	1/8		NP_006114.1
IDS	NM_001166550.4	c.-205_-190del		5_prime_UTR_variant	1/9		NP_001160022.1
IDS	NR_104128.2	n.191_206del		non_coding_transcript_exon_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDS	ENST00000340855.11	c.22_37del	p.Arg8TrpfsTer5	frameshift_variant	1/9	1	NM_000202.8	ENSP00000339801	P1

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-II Pathogenic:2

Pathogenic, criteria provided, single submitter	literature only	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	Jun 07, 2024	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) -
Pathogenic, criteria provided, single submitter	research	IIFP, CONICET-UNLP	May 16, 2012	- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs864622775; hg19: chrX-148586630;