rs1557338131

Positions:

• chrX-149487006-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000202.8(IDS):​c.1099A>T​(p.Thr367Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: IDS NM_000202.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 B:1
• Conservation: PhyloP100: 5.27

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDS	NM_000202.8	c.1099A>T	p.Thr367Ser	missense_variant	8/9	ENST00000340855.11	NP_000193.1
IDS	NM_001166550.4	c.829A>T	p.Thr277Ser	missense_variant	8/9		NP_001160022.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDS	ENST00000340855.11	c.1099A>T	p.Thr367Ser	missense_variant	8/9	1	NM_000202.8	ENSP00000339801.6
ENSG00000241489	ENST00000651111.1	c.466A>T	p.Thr156Ser	missense_variant	13/14			ENSP00000498395.1
ENSG00000241489	ENST00000422081.6	c.466A>T	p.Thr156Ser	missense_variant	8/9	2		ENSP00000477056.1
ENSG00000241489	ENST00000441880.1	n.206A>T		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mucopolysaccharidosis, MPS-II Pathogenic:1 Benign:1

Likely pathogenic, criteria provided, single submitter	literature only	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	Jun 07, 2024	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_Strong) -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Nov 06, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	23
DANN	Benign	0.94
DEOGEN2	Pathogenic	0.85	D;.
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.47	T;T
M_CAP	Pathogenic	0.76	D
MetaRNN	Uncertain	0.54	D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Benign	1.1	L;.
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.6	D;.
REVEL	Uncertain	0.64
Sift	Benign	0.20	T;.
Sift4G	Benign	0.25	T;T
Polyphen		0.62	P;.
Vest4		0.41
MutPred		0.45		Gain of disorder (P = 0.0446);.;
MVP		0.93
MPC		0.50
ClinPred		0.89	D
GERP RS		5.3
Varity_R		0.72
gMVP		0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs1557338131; hg19: chrX-148568537;