rs113993953

Variant names:

• chrX-149490436-T-A
• rs113993953
• NM_000202.8:c.884A>T

Your query was ambiguous. Multiple possible variants found:

• chrX-149490436-T-A
• chrX-149490436-T-C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_000202.8(IDS):​c.884A>T​(p.Lys295Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K295R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: IDS NM_000202.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 0.882
• Publications: 5 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_000202.8
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91
• PP5: Variant X-149490436-T-A is Pathogenic according to our data. Variant chrX-149490436-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 221212.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDS	NM_000202.8	c.884A>T	p.Lys295Ile	missense_variant	Exon 7 of 9	ENST00000340855.11	NP_000193.1
IDS	NM_001166550.4	c.614A>T	p.Lys205Ile	missense_variant	Exon 7 of 9		NP_001160022.1
IDS	NM_006123.5	c.884A>T	p.Lys295Ile	missense_variant	Exon 7 of 8		NP_006114.1
IDS	NR_104128.2	n.1183A>T		non_coding_transcript_exon_variant	Exon 8 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDS	ENST00000340855.11	c.884A>T	p.Lys295Ile	missense_variant	Exon 7 of 9	1	NM_000202.8	ENSP00000339801.6
ENSG00000241489	ENST00000651111.1	c.251A>T	p.Lys84Ile	missense_variant	Exon 12 of 14			ENSP00000498395.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mucopolysaccharidosis, MPS-II Pathogenic:1 Uncertain:1

Feb 26, 2008

IIFP, CONICET-UNLP

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 07, 2024

Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: literature only

Absent from controls (or at low frequency) in gnomAD database (PM2_Moderate), Missense variant in a gene with a low rate of benign missense variation (PP2_Supporting), Patient’s phenotype or family history highly specific for the disease (PP4_Moderate) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D;.;.
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.2	M;M;.
PhyloP100		0.88
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.5	D;D;.
REVEL	Pathogenic	0.75
Sift	Benign	0.049	D;D;.
Sift4G	Benign	0.074	T;T;T
Polyphen		0.94	P;P;.
Vest4		0.63
MutPred		0.56		Gain of stability (P = 0.0076);Gain of stability (P = 0.0076);.;
MVP		0.93
MPC		0.68
ClinPred		0.97	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74
gMVP		0.80
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs113993953; hg19: chrX-148571967;