rs1557340558

Variant names:

• chrX-149505034-CCTGTGGTCGAGTTGGCCTGCGTTTCGGATCCGAGGGCGACGCAGACGGAGCTCAGAACCAGACCCAGCCAGAGAAGGCCTCGGCCGGTCCGGGGTGGCGGCATTTCGGCTTCGACGCGGCCGCTTCAGAGCGGCGGGGACAGGCTGCAGCAGGTGGCGCAGTTAGCAGCCGCCGCCGCAGCCACAGAGACCTCCTCGTCGGGAACCCATGAAGACTGCGCAACACAGCCGCCGCCCGGGCCCGCAGGCCCGGGCGCTGGCCGCAGCGCGAGTGCGTCCGTGCGACTCTTCCCTGCGTCCCTCCCCTCCGGGGCGGGTTCT-C
• rs1557340558
• NM_000202.8:c.-217_103del

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP5_Moderate

The NM_000202.8(IDS):​c.-217_103del variant causes a 5 prime UTR truncation, exon loss change involving the alteration of a non-conserved nucleotide. 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 DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: IDS NM_000202.8 5_prime_UTR_truncation, exon_loss
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.63
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PP5: Variant X-149505034-CCTGTGGTCGAGTTGGCCTGCGTTTCGGATCCGAGGGCGACGCAGACGGAGCTCAGAACCAGACCCAGCCAGAGAAGGCCTCGGCCGGTCCGGGGTGGCGGCATTTCGGCTTCGACGCGGCCGCTTCAGAGCGGCGGGGACAGGCTGCAGCAGGTGGCGCAGTTAGCAGCCGCCGCCGCAGCCACAGAGACCTCCTCGTCGGGAACCCATGAAGACTGCGCAACACAGCCGCCGCCCGGGCCCGCAGGCCCGGGCGCTGGCCGCAGCGCGAGTGCGTCCGTGCGACTCTTCCCTGCGTCCCTCCCCTCCGGGGCGGGTTCT-C is Pathogenic according to our data. Variant chrX-149505034-CCTGTGGTCGAGTTGGCCTGCGTTTCGGATCCGAGGGCGACGCAGACGGAGCTCAGAACCAGACCCAGCCAGAGAAGGCCTCGGCCGGTCCGGGGTGGCGGCATTTCGGCTTCGACGCGGCCGCTTCAGAGCGGCGGGGACAGGCTGCAGCAGGTGGCGCAGTTAGCAGCCGCCGCCGCAGCCACAGAGACCTCCTCGTCGGGAACCCATGAAGACTGCGCAACACAGCCGCCGCCCGGGCCCGCAGGCCCGGGCGCTGGCCGCAGCGCGAGTGCGTCCGTGCGACTCTTCCCTGCGTCCCTCCCCTCCGGGGCGGGTTCT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 221979.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.-217_103del		5_prime_UTR_truncation, exon_loss_variant	Exon 1 of 9	ENST00000340855.11	NP_000193.1
IDS	NM_000202.8	c.-217_103del		exon_loss_variant, splice_region_variant	Exon 1 of 9	ENST00000340855.11	NP_000193.1
IDS	NM_000202.8	c.-217_103del		upstream_gene_variant		ENST00000340855.11	NP_000193.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDS	ENST00000340855.11	c.-217_103del		5_prime_UTR_truncation, exon_loss_variant	Exon 1 of 9	1	NM_000202.8	ENSP00000339801.6
IDS	ENST00000340855.11	c.-217_103del		exon_loss_variant, splice_region_variant	Exon 1 of 9	1	NM_000202.8	ENSP00000339801.6
ENSG00000241489	ENST00000651111.1	c.-215-4317_-215-3998del		intron_variant	Intron 8 of 13			ENSP00000498395.1
IDS	ENST00000340855.11	c.-217_103del		upstream_gene_variant		1	NM_000202.8	ENSP00000339801.6

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:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mucopolysaccharidosis, MPS-II Pathogenic:1

Oct 18, 2015

MOLECULAR BIOLOGY LABORATORY, INSTITUTO NACIONAL DE PEDIATRIA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Pathogenic variation identified in a Hunter syndrome male patient with I2S deficiency. He presents mental retardation, but no seizures, nor hydrocephaly. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=40/60	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1557340558; hg19: chrX-148586564;