rs113993948

Variant names:

• chrX-149486983-G-A
• rs113993948
• NM_000202.8:c.1122C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-149486983-G-A
• chrX-149486983-G-T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM2 PP3_Moderate PP5_Very_Strong

The NM_000202.8(IDS):​c.1122C>T​(p.Gly374Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000628120: Studies have shown that this variant results in the activation of a cryptic splice site in exon 8 (PMID:8940265, 26407519, 26693516)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. G374G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: IDS NM_000202.8 synonymous
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 O:2
• Conservation: PhyloP100: -0.137
• Publications: 27 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 Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, 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 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000628120: Studies have shown that this variant results in the activation of a cryptic splice site in exon 8 (PMID: 8940265, 26407519, 26693516).; SCV004101336: Functional studies show that the c.1122C>T variant results in activation of a cryptic splice site within exon 8 of the IDS gene leading to a deletion of 20 amino acids (PMID: 8940265; 26407519; 26693516).; SCV005203964: The variant was absent in 183469 control chromosomes. c.1122C>T has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type II (Hunter Syndrome) (e.g. Rathman_1996, Gort_1998, Uttarilli_2016). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 9452044, 26407519, 8940265, 27146977). no; SCV002574624: Published functional studies demonstrate that this variant creates a new splice donor site resulting in skipping of the last 60 nucleotides of exon 8 (Matos et al. 2015)
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-149486983-G-A is Pathogenic according to our data. Variant chrX-149486983-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 10491.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000202.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDS	NM_000202.8	MANE Select	c.1122C>T	p.Gly374Gly	synonymous	Exon 8 of 9	NP_000193.1	P22304-1
	IDS	NM_001166550.4		c.852C>T	p.Gly284Gly	synonymous	Exon 8 of 9	NP_001160022.1	B4DGD7
	IDS	NM_006123.5		c.*305C>T		downstream_gene	N/A	NP_006114.1	P22304-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDS	ENST00000340855.11	TSL:1 MANE Select	c.1122C>T	p.Gly374Gly	synonymous	Exon 8 of 9	ENSP00000339801.6	P22304-1
	ENSG00000241489	ENST00000651111.1		c.489C>T	p.Gly163Gly	synonymous	Exon 13 of 14	ENSP00000498395.1	B3KWA1
	IDS	ENST00000875674.1		c.1203C>T	p.Gly401Gly	synonymous	Exon 9 of 10	ENSP00000545733.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 1

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
10	-	-	Mucopolysaccharidosis, MPS-II (12)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	19
DANN	Benign	0.82
PhyloP100		-0.14
Mutation Taster		=100/0	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.94		Position offset: 2

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

Other links and lift over

dbSNP: rs113993948; hg19: chrX-148568514; COSMIC: COSV61711594; COSMIC: COSV61711594;