X-149496392-G-GCTTCCCTTAAACAT

Position:

• chrX-149496392-G-GCTTCCCTTAAACAT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000202.8(IDS):​c.832_833insATGTTTAAGGGAAG​(p.Ala278fs) variant causes a frameshift, stop gained change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: IDS NM_000202.8 frameshift, stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.68

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]

ENSG00000241489 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 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-149496392-G-GCTTCCCTTAAACAT is Pathogenic according to our data. Variant chrX-149496392-G-GCTTCCCTTAAACAT is described in ClinVar as [Pathogenic]. Clinvar id is 198059.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDS	NM_000202.8	c.832_833insATGTTTAAGGGAAG	p.Ala278fs	frameshift_variant, stop_gained	6/9	ENST00000340855.11	NP_000193.1
IDS	NM_001166550.4	c.562_563insATGTTTAAGGGAAG	p.Ala188fs	frameshift_variant, stop_gained	6/9		NP_001160022.1
IDS	NM_006123.5	c.832_833insATGTTTAAGGGAAG	p.Ala278fs	frameshift_variant, stop_gained	6/8		NP_006114.1
IDS	NR_104128.2	n.1001_1002insATGTTTAAGGGAAG		non_coding_transcript_exon_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDS	ENST00000340855.11	c.832_833insATGTTTAAGGGAAG	p.Ala278fs	frameshift_variant, stop_gained	6/9	1	NM_000202.8	ENSP00000339801.6
ENSG00000241489	ENST00000651111.1	c.199_200insATGTTTAAGGGAAG	p.Ala67fs	frameshift_variant, stop_gained	11/14			ENSP00000498395.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

May 23, 2014

- -

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: rs797044770; hg19: chrX-148577923;