X-149500991-AAA-ACCAGCTATACGG

Position:

• chrX-149500991-AAA-ACCAGCTATACGG

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.463_464delinsCCGTATAGCTGG​(p.Phe155ProfsTer12) variant causes a frameshift change. 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. F155F) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: IDS NM_000202.8 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.58

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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-149500992-AA-CCAGCTATACGG is Pathogenic according to our data. Variant chrX-149500992-AA-CCAGCTATACGG is described in ClinVar as [Pathogenic]. Clinvar id is 221973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDS	NM_000202.8	c.463_464delinsCCGTATAGCTGG	p.Phe155ProfsTer12	frameshift_variant	4/9	ENST00000340855.11
IDS	NM_001166550.4	c.193_194delinsCCGTATAGCTGG	p.Phe65ProfsTer12	frameshift_variant	4/9
IDS	NM_006123.5	c.463_464delinsCCGTATAGCTGG	p.Phe155ProfsTer12	frameshift_variant	4/8
IDS	NR_104128.2	n.632_633delinsCCGTATAGCTGG		non_coding_transcript_exon_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDS	ENST00000340855.11	c.463_464delinsCCGTATAGCTGG	p.Phe155ProfsTer12	frameshift_variant	4/9	1	NM_000202.8	P1

Frequencies

GnomAD3 genomes Cov.: 23

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

GnomAD4 genome Cov.: 23

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_Strong) -
Pathogenic, criteria provided, single submitter	research	MOLECULAR BIOLOGY LABORATORY, INSTITUTO NACIONAL DE PEDIATRIA	Oct 18, 2015	Pathogenic variation identified in a Hunter syndrome male patient with I2S deficiency. He presents mental retardation, but no seizures, nor hydrocephaly. Pathogenic variation was inherited through a maternal mixed somatic and germline mosaicism. -

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: rs869025304; hg19: chrX-148582523;