rs113993955

chrX-149504216-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000202.8(IDS):c.181T>C(p.Ser61Pro) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S61F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: IDS NM_000202.8 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.46

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000202.8
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938
• PP5: Variant X-149504216-A-G is Pathogenic according to our data. Variant chrX-149504216-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 221205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-149504216-A-G is described in Lovd as [Pathogenic]. Variant chrX-149504216-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDS	NM_000202.8	c.181T>C	p.Ser61Pro	missense_variant	2/9	ENST00000340855.11
IDS	NM_006123.5	c.181T>C	p.Ser61Pro	missense_variant	2/8
IDS	NM_001166550.4	c.-46T>C		5_prime_UTR_variant	2/9
IDS	NR_104128.2	n.350T>C		non_coding_transcript_exon_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDS	ENST00000340855.11	c.181T>C	p.Ser61Pro	missense_variant	2/9	1	NM_000202.8	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-II Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Pathogenic, criteria provided, single submitter	research	IIFP, CONICET-UNLP	Jan 27, 2010	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.69
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.;D;.
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.3	M;M;.;.
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.2	D;D;D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0050	D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;.
Polyphen		1.0	D;D;D;.
Vest4		0.90
MutPred		0.68		Gain of catalytic residue at S61 (P = 0.0028);Gain of catalytic residue at S61 (P = 0.0028);Gain of catalytic residue at S61 (P = 0.0028);Gain of catalytic residue at S61 (P = 0.0028);
MVP		1.0
MPC		2.5
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.96
gMVP		1.0

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: rs113993955; hg19: chrX-148585746;