rs797044770

Variant names:

• chrX-149496392-G-GCTTCCCTTAAACAT
• rs797044770
• NM_000202.8:c.832_833insATGTTTAAGGGAAG

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_000202.8(IDS):​c.832_833insATGTTTAAGGGAAG​(p.Ala278AspfsTer3) variant causes a frameshift, stop gained change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A278A) 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, stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.68
• Publications: 0 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 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant X-149496392-G-GCTTCCCTTAAACAT is Pathogenic according to our data. Variant chrX-149496392-G-GCTTCCCTTAAACAT is described in ClinVar as Pathogenic. ClinVar VariationId is 198059.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDS	NM_000202.8	c.832_833insATGTTTAAGGGAAG	p.Ala278AspfsTer3	frameshift_variant, stop_gained	Exon 6 of 9	ENST00000340855.11	NP_000193.1
IDS	NM_001166550.4	c.562_563insATGTTTAAGGGAAG	p.Ala188AspfsTer3	frameshift_variant, stop_gained	Exon 6 of 9		NP_001160022.1
IDS	NM_006123.5	c.832_833insATGTTTAAGGGAAG	p.Ala278AspfsTer3	frameshift_variant, stop_gained	Exon 6 of 8		NP_006114.1
IDS	NR_104128.2	n.1001_1002insATGTTTAAGGGAAG		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.832_833insATGTTTAAGGGAAG	p.Ala278AspfsTer3	frameshift_variant, stop_gained	Exon 6 of 9	1	NM_000202.8	ENSP00000339801.6
ENSG00000241489	ENST00000651111.1	c.199_200insATGTTTAAGGGAAG	p.Ala67AspfsTer3	frameshift_variant, stop_gained	Exon 11 of 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

May 23, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs797044770; hg19: chrX-148577923;